Escolar Documentos
Profissional Documentos
Cultura Documentos
Contents
1
Retrovirus
1.1
Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2
Multiplication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3
Transmission
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.4
Genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.5
Provirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.6
Early evolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.7
Gene therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.8
Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.9
Classication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.9.1
Exogenous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.9.2
Endogenous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.10 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.12 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Lentivirus
2.1
Classication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2
Morphology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3
2.4
Proteome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5
Antigenic properties
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.6
Biological . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.7
2.8
Practical applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.9
Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.10 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1
History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
i
ii
CONTENTS
3.2
Tropism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3
Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
3.5
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
3.6
External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
HIV
4.1
12
Virology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
4.1.1
Classication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
4.1.2
12
4.1.3
Tropism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
4.1.4
Replication cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
4.1.5
17
4.1.6
Genetic variability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17
4.2
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
18
4.3
Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19
4.4
History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19
4.4.1
Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19
4.4.2
Origins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
4.5
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
4.6
References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
4.7
Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
4.8
External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
History of HIV/AIDS
27
5.1
27
5.1.1
. . . . . . . . . . . . . . . . . . . . . .
27
5.1.2
28
5.1.3
Bushmeat practice
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29
5.2.1
29
5.2.2
29
5.3
33
5.4
History of spread . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
5.4.1
33
5.4.2
33
5.4.3
33
5.4.4
33
5.4.5
34
5.4.6
34
5.4.7
34
5.4.8
34
5.2
Emergence
CONTENTS
5.4.9
34
35
5.5.1
35
5.5.2
35
5.5.3
35
5.5.4
35
5.5.5
Nobel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
35
5.6
Classication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
35
5.7
Genetic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
35
5.8
Discredited hypotheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
35
5.9
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
36
5.10 Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
36
HIV/AIDS denialism
40
6.1
History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
40
6.1.1
U.S. courts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
41
6.1.2
South Africa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
41
6.2
42
6.3
42
6.3.1
Former denialists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
43
6.3.2
44
44
6.4.1
44
6.4.2
46
6.5
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
6.6
Footnotes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
6.7
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
51
6.8
Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
51
6.9
External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
51
5.5
6.4
Subtypes of HIV
52
7.1
Major types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
52
7.1.1
HIV-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
52
7.1.2
HIV-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
53
Evolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
54
7.2.1
54
7.3
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
54
7.4
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
54
7.5
External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
55
7.2
iii
HIV/AIDS
8.1
56
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56
iv
CONTENTS
8.2
8.1.1
Acute infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56
8.1.2
Clinical latency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
57
8.1.3
57
Transmission
58
8.2.1
Sexual
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
58
8.2.2
Body uids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
58
8.2.3
Mother-to-child
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
59
8.3
Virology
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
59
8.4
Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
60
8.5
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
60
8.5.1
HIV testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
61
8.5.2
Classications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
61
Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
62
8.6.1
Sexual contact
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
62
8.6.2
Pre-exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
62
8.6.3
Post-exposure
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
62
8.6.4
Mother-to-child
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
63
8.6.5
Vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
63
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
63
8.7.1
Antiviral therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
63
8.7.2
Opportunistic infections
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
64
8.7.3
Diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
64
8.7.4
Alternative medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
64
8.8
Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
64
8.9
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
65
8.6
8.7
8.10 History
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
66
8.10.1 Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
66
8.10.2 Origins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
66
67
8.11.1 Stigma
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
67
68
68
69
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
69
8.11.6 Misconceptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
69
8.12 Research
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
69
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
70
80
81
Pathophysiology of HIV/AIDS
82
9.1
82
8.13 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Immunology
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTENTS
9.2
Cells aected . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
83
9.3
The eect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
83
9.4
Molecular basis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
83
9.5
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
83
10 Diagnosis of HIV/AIDS
84
84
10.2 Terminology
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
84
10.3 Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
84
84
85
85
10.3.4 Condentiality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
85
85
85
85
10.4.2 ELISA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
86
86
86
87
87
88
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
88
88
10.7 Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
89
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
89
10.9 Criticisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
89
89
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
90
10.10Fraudulent testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
90
10.11References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
90
10.12External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
92
11 Prevention of HIV/AIDS
93
93
11.1.1 Pharmaceutical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
93
94
94
94
95
95
vi
CONTENTS
11.1.7 Follow-up care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
95
11.1.8 Mother-to-child
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
95
11.1.9 Vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
95
95
96
11.2 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
96
11.2.1 1980s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
96
96
97
97
11.4 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
97
102
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
CONTENTS
vii
114
121
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Chapter 1
Retrovirus
Retrovirology redirects here. For the journal, see 1.1 Structure
Retrovirology (journal).
For a more accessible and less technical introduction to Virions of retroviruses consist of enveloped particles
this topic, see Introduction to viruses.
about 100 nm in diameter. The virions also contain two
identical single-stranded RNA molecules 710 kilobases
Retroviridae is a family of enveloped viruses that repli- in length. Although virions of dierent retroviruses do
cate in a host cell through the process of reverse tran- not have the same morphology or biology, all the virion
[2]
scription. A retrovirus is a single-stranded positive- components are very similar.
sense RNA virus with a DNA intermediate and, as an The main virion components are:
obligate parasite, targets a host cell. Once inside the host
cell cytoplasm, the virus uses its own reverse transcrip Envelope: composed of lipids (obtained from the
tase enzyme to produce DNA from its RNA genome
host plasma membrane during budding process) as
the reverse of the usual pattern, thus retro (backwards).
well
as glycoprotein encoded by the env gene. The
This new DNA is then incorporated into the host cell
retroviral
envelope serves three distinct functions:
genome by an integrase enzyme, at which point the retroprotection
from the extracellular environment via
viral DNA is referred to as a provirus. The host cell then
the
lipid
bilayer,
enabling the retrovirus to enter/exit
treats the viral DNA as part of its own genome, translathost
cells
through
endosomal membrane tracking,
ing and transcribing the viral genes along with the cells
and
the
ability
to
directly
enter cells by fusing with
own genes, producing the proteins required to assemble
their
membranes.
new copies of the virus. It is dicult to detect the virus
until it has infected the host. At that point, the infection
RNA: consists of a dimer RNA. It has a cap at the
will persist indenitely.
5' end and a poly(A) tail at the 3' end. The RNA
In most viruses, DNA is transcribed into RNA, and then
genome also has terminal noncoding regions, which
RNA is translated into protein. However, retroviruses
are important in replication, and internal regions
function dierently their RNA is reverse-transcribed
that encode virion proteins for gene expression. The
into DNA, which is integrated into the host cells genome
5' end includes four regions, which are R, U5, PBS,
(when it becomes a provirus), and then undergoes the
and L. The R region is a short repeated sequence
usual transcription and translational processes to express
at each end of the genome used during the reverse
the genes carried by the virus. So, the information contranscription to ensure correct end-to-end transfer in
tained in a retroviral gene is used to generate the corthe growing chain. U5, on the other hand, is a short
responding protein via the sequence: RNA DNA
unique sequence between R and PBS. PBS (primer
RNA polypeptide. This extends the fundamental probinding site) consists of 18 bases complementary to
cess identied by Francis Crick (one gene-one peptide)
3' end of tRNA primer. L region is an untranslated
in which the sequence is: DNA RNA peptide (proleader region that gives the signal for packaging of
teins are made of one or more polypeptide chain; e.g.
the genome RNA. The 3' end includes 3 regions,
haemoglobin is a four-chain peptide).
which are PPT (polypurine tract), U3, and R. The
Retroviruses are valuable research tools in molecular biPPT is a primer for plus-strand DNA synthesis durology, and have been used successfully in gene delivery
ing reverse transcription. U3 is a sequence between
systems.[1]
PPT and R, which serves as a signal that the provirus
can use in transcription. R is the terminal repeated
sequence at 3' end.
Proteins: consisting of gag proteins, protease (PR),
pol proteins, and env proteins.
1
CHAPTER 1. RETROVIRUS
Group-specic antigen (gag) proteins are major components of the viral capsid, which are
about 20004000 copies per virion.
Protease is expressed dierently in dierent
viruses. It functions in proteolytic cleavages
during virion maturation to make mature gag
and pol proteins.
Pol proteins are responsible for synthesis of viral DNA and integration into host DNA after
infection.
Env proteins play a role in association and entry of virions into the host cell.[3] Possessing a
functional copy of an env gene is what makes
retroviruses distinct from retroelements.[4]
The ability of the retrovirus to bind to its target host cell using specic cell-surface receptors is given by the surface component (SU)
of the Env protein, while the ability of the
retrovirus to enter the cell via membrane fusion is imparted by the membrane-anchored
trans-membrane component (TM). Thus the
Env protein is what enables the retrovirus to
be infectious.
1.2 Multiplication
generation. These endogenous retroviruses (ERVs), contrasted with exogenous ones, now make up 5-8% of the
human genome.[5] Most insertions have no known function and are often referred to as "junk DNA". However, many endogenous retroviruses play important roles
in host biology, such as control of gene transcription, cell
fusion during placental development in the course of the
germination of an embryo, and resistance to exogenous
retroviral infection. Endogenous retroviruses have also
received special attention in the research of immunologyrelated pathologies, such as autoimmune diseases like
multiple sclerosis, although endogenous retroviruses have
not yet been proven to play any causal role in this class of
disease.[6]
While transcription was classically thought to occur only
from DNA to RNA, reverse transcriptase transcribes
RNA into DNA. The term retro in retrovirus refers to
this reversal (making DNA from RNA) of the central
dogma of molecular biology. Reverse transcriptase activity outside of retroviruses has been found in almost
all eukaryotes, enabling the generation and insertion of
new copies of retrotransposons into the host genome.
These inserts are transcribed by enzymes of the host
into new RNA molecules that enter the cytosol. Next,
some of these RNA molecules are translated into viral
proteins. For example, the gag gene is translated into
molecules of the capsid protein, the pol gene is translated
into molecules of reverse transcriptase, and the env gene
is translated into molecules of the envelope protein. It is
important to note that a retrovirus must bring its own
reverse transcriptase in its capsid, otherwise it is unable
to utilize the enzymes of the infected cell to carry out the
task, due to the unusual nature of producing DNA from
RNA.
Industrial drugs that are designed as protease and reverse
transcriptase inhibitors are made such that they target
specic sites and sequences within their respective enzymes. However these drugs can quickly become ineffective due to the fact that the gene sequences that code
for the protease and the reverse transcriptase quickly mutate. These changes in bases cause specic codons and
sites with the enzymes to change and thereby avoid drug
targeting by losing the sites that the drug actually targets.
Because reverse transcription lacks the usual
proofreading of DNA replication, a retrovirus mutates
very often. This enables the virus to grow resistant
to antiviral pharmaceuticals quickly, and impedes the
development of eective vaccines and inhibitors for the
retrovirus.[7]
1.3 Transmission
Cell-to-cell[8]
Fluids
Airborne, like the Jaagsiekte sheep retrovirus.
1.4 Genes
Retrovirus genomes commonly contain these three open
reading frames that encode for proteins that can be found
in the mature virus:
1.8 Cancer
group-specic antigen (gag) codes for core and struc- Retroviruses that cause tumor growth include Rous sarcoma virus and Mouse mammary tumor virus. Cancer
tural proteins of the virus;
can be triggered by proto-oncogenes that were mistak polymerase (pol) codes for reverse transcriptase, enly incorporated into proviral DNA or by the disruption
of cellular proto-oncogenes. Rous sarcoma virus contains
protease and integrase;
the src gene that triggers tumor formation. Later it was
found that a similar gene in cells is involved in cell sig envelope (env) codes for the retroviral coat proteins.
naling, which was most likely excised with the proviral
DNA. Nontransforming viruses can randomly insert their
DNA into proto-oncogenes, disrupting the expression of
proteins that regulate the cell cycle. The promoter of the
1.5 Provirus
provirus DNA can also cause over expression of regulatory genes.
This DNA can be incorporated into host genome as a
provirus that can be passed on to progeny cells. The retrovirus DNA is inserted at random into the host genome.
Because of this, it can be inserted into oncogenes. In this
way some retroviruses can convert normal cells into can- 1.9 Classication
cer cells. Some provirus remains latent in the cell for a
long period of time before it is activated by the change in
cell environment.
Delta-retroviruses
*
Epsilon-retroviruses
(simple)
SnRV
HERV-W
Gammaretroviruses*
PERV
(simple) GALV
(complex)
BLV
HTLV-II
WDSV
Lentiviruses
EIAV (complex)
FIV
HIV-2
SIVmac
HTLV-I
MLV
HIV-1
MVV
AlphaALV retroviruses*
RSV (simple)
JRSV
HERV-K
SRV
MMTV
Beta-retroviruses*
(simple)
CHAPTER 1. RETROVIRUS
1.9.1
Exogenous
as the template during genome replication. Virally encoded reverse transcriptase uses the pre-genomic RNA
These are infectious RNA-containing viruses which are as a template for the creation of genomic DNA.
transmitted from human to human.
Group VII includes:
The following genera are included here:
Family Hepadnaviridae e.g. Hepatitis B virus
Genus Alpharetrovirus; type species: Avian leukosis
Family Caulimoviridae e.g. Cauliower mosaic
virus; others include Rous sarcoma virus
virus
Genus Betaretrovirus; type species: Mouse mammary tumour virus
1.9.2 Endogenous
These were previously divided into three subfamilies (On- 1.10 Treatment
covirinae, Lentivirinae, and Spumavirinae), but are now
divided into two: Orthoretrovirinae and SpumaretroviriAntiretroviral drugs are medications for the treatment
nae. The term oncovirus is now commonly used to deof infection by retroviruses, primarily HIV. Dierent
scribe a cancer-causing virus.
classes of antiretroviral drugs act on dierent stages of
Retroviruses were in 2 groups of the Virus classica- the HIV life cycle. Combination of several (typically
tion#Baltimore classication.
three or four) antiretroviral drugs is known as highly active anti-retroviral therapy (HAART).[10]
Group VI viruses
All members of Group VI use virally encoded reverse 1.11 Treatment of veterinary retrotranscriptase, an RNA-dependent DNA polymerase, to
viruses
produce DNA from the initial virion RNA genome. This
DNA is often integrated into the host genome, as in the
Feline leukemia virus and Feline immunodeciency virus
case of retroviruses and pseudoviruses, where it is repliinfections are treated with biologics, including the only
cated and transcribed by the host.
immunomodulator currently licensed for sale in the
Group VI includes:
United States, Lymphocyte T-Cell Immune Modulator
(LTCI).[11]
Family Metaviridae
Family Pseudoviridae
Family Retroviridae Retroviruses, e.g. HIV
Group VII viruses
Both families in Group VII have DNA genomes contained within the invading virus particles. The DNA
genome is transcribed into both mRNA, for use as a transcript in protein synthesis, and pre-genomic RNA, for use
1.12 References
[1] Kurth, Reinhard; Bannert, Norbert, eds.
(2010).
Retroviruses: Molecular Biology, Genomics and Pathogenesis. Horizon Scientic. ISBN 978-1-904455-55-4.
[2] Con, John M. (1992). Structure and Classication of
Retroviruses. In Levy, Jay A. The Retroviridae 1 (1st
ed.). New York: Plenum. p. 20. ISBN 0-306-44074-1.
[3] Con 1992, pp. 2634
Chapter 2
Lentivirus
Lentivirus (lente-, Latin for "slow") is a genus of viruses
of the Retroviridae family, characterized by a long
incubation period.[1] Lentiviruses can deliver a signicant
amount of viral RNA into the DNA of the host cell and
have the unique ability among retroviruses of being able
to infect non-dividing cells, so they are one of the most
ecient methods of a gene delivery vector.[2] HIV, SIV,
FIV, EIAV, and Visna are all examples of lentiviruses.[1]
2.1 Classication
Five serogroups of lentiviruses are recognized, reecting the vertebrate hosts with which they are associated
(primates, sheep and goats, horses, cats, and cattle).[3]
The primate lentiviruses are distinguished by the use of
CD4 protein as a receptor and the absence of dUTPase.[4]
Some groups have cross-reactive gag antigens (e.g., the
ovine, caprine and feline lentiviruses). Antibodies to
gag antigens in lions and other large felids indicate
the existence of other viruses related to FIV and the
ovine/caprine lentiviruses.
2.4 Proteome
2.2 Morphology
and
4. P17 non-glycosylated matrix protein MA, also encoded by gag. 4th largest 17000 Da.
5. Non-glycosylated capsid protein NC, also encoded
by gag. 5th largest 7000-11000 Da.
6
2.6 Biological
properties
Another common application is to use a lentivirus to introduce a new gene into human or animal cells. For exam General
ple, a model of mouse hemophilia is corrected by expressing wild-type platelet-factor VIII, the gene that is mutated
Buoyant density 1.161.18 g cm3 in sucrose in human hemophilia.[8] Lentiviral infection has advan Virions sensitive to heat, detergents, and tages over other gene-therapy methods including highformaldehyde
eciency infection of dividing and non-dividing cells,
CHAPTER 2. LENTIVIRUS
long-term stable expression of a transgene, and low immunogenicity. Lentiviruses have also been successfully
used for transfection of diabetic mice with the gene encoding PDGF (platelet-derived growth factor),[9] a therapy being considered for use in humans. These treatments, like most current gene therapy experiments, show
promise but are yet to be established as safe and eective in controlled human studies. Gammaretroviral and
lentiviral vectors have so far been used in more than 300
clinical trials, addressing treatment options for various
diseases.[10]
2.10 References
Ryan KJ, Ray CG, ed. (2004). Sherris Medical Microbiology: An Introduction to Infectious Diseases
(4th ed.). New York: McGraw Hill. ISBN 0-83858529-9.
Desport, M, ed.
(2010).
Lentiviruses and
Macrophages: Molecular and Cellular Interactions.
Caister Academic Press. ISBN 978-1-904455-608.
2.9 Notes
[1] What is Lentivirus?". News-Medical.net. https://
plus.google.com/109000124032577298634/. Retrieved
2015-11-30.
[2] Cockrell, Adam S.; Kafri, Tal (2007-07-01). Gene delivery by lentivirus vectors. Molecular Biotechnology 36
(3): 184204. ISSN 1073-6085. PMID 17873406.
[3] Mahy, Brian W. J. (2009-02-26). The Dictionary of Virology. Academic Press. ISBN 9780080920368.
[4] Piguet, V.; Schwartz, O.; Le Gall, S.; Trono, D. (1999-0401). The downregulation of CD4 and MHC-I by primate
lentiviruses: a paradigm for the modulation of cell surface
receptors. Immunological Reviews 168: 5163. ISSN
0105-2896. PMID 10399064.
[5] ViralZone: Lentivirus. viralzone.expasy.org. Retrieved
2015-11-30.
Chapter 3
3.2 Tropism
Dierences in species specicity of SIV and related retroviruses may be partly explained by variants of the protein TRIM5 in humans and non-human primate species.
This intracellular protein recognizes the capsid of various
retroviruses and blocks their reproduction. Other proVirus strains from two of these primate species, SIVsmm teins such as APOBEC3G/3F may also be important in
in sooty mangabeys and SIVcpz in chimpanzees, are be- restricting cross-species transmission.
lieved to have crossed the species barrier into humans,
resulting in HIV-2 and HIV-1, respectively. The most
likely route of transmission of HIV-1 to humans involves
contact with the blood of chimps that are often hunted 3.3 Research
for bushmeat in Africa.[3]
Unlike HIV-1 and HIV-2 infections in humans, SIV in- SHIV, a virus combining parts of the HIV and SIV
fections in their natural hosts appear in many cases to be genomes, was created for various research purposes, inrespond
non-pathogenic. Extensive studies in sooty mangabeys cluding analyzing how dierent parts of the virus
[9]
to
dierent
antimicrobial
drugs
and
vaccines.
have established that SIVsmm infection does not cause
any disease in these animals, despite high levels of circulating virus. However, if this virus infects an Asian or
Indian rhesus macaque, the animal will develop simian
AIDS (SAIDS).[5] A recent study of SIVcpz in wild living
chimpanzees suggests that infected chimpanzees experience an AIDS-like illness similar to HIV-1 infected humans. The later stages of SIV infection turn into SAIDS,
much as HIV infection turns into AIDS.
10
females were less likely to give birth, could pass the virus
to their infants, and had a higher infant mortality rate than
uninfected females.[10][11]
The ICTVdB code of SIV is 61.0.6.5.003.[12]
In 2010, researchers reported that SIV had infected
monkeys in Bioko for at least 32,000 years. Based on
molecular clock analyses of sequences, it was previously
thought by many that SIV infection in monkeys had happened over the past few hundred years.[13] Scientists estimated that it would take a similar amount of time before
humans would adapt naturally to HIV infection in the way
monkeys in Africa have adapted to SIV and not suer any
harm from the infection.[14]
In 2012, researchers reported that initial infection
of Rhesus monkeys by neutralization-resistant SIV
strains[15] could be partially prevented through use of an
anti-SIVSME vaccine obligately including Env protein
antigens.[16]
In 2013, a study by a group of authors reported on
successful testing of a vaccine containing SIV proteinexpressing rhesus cytomegalovirus vector. Approximately 50% of vaccinated rhesus macaques manifested
durable, aviraemic control of infection with the highly
pathogenic strain SIVmac239.[17]
Bonobos appear to avoid simian immunodeciency virus
(SIV) and its eects, though it is not known why.[18]
3.5 References
[1] Peeters, M.; Courgnaud, V.; Abela, B. (2001). Genetic
Diversity of Lentiviruses in Non-Human Primates
(PDF). AIDS Reviews 3: 310. Retrieved 2010-09-19.
[2] Peeters, M.; Courgnaud, V. (2002). Overview of Primate Lentiviruses and their Evolution in Non-human Primates in Africa (PDF). In C. Kuiken, B. Foley, E. Freed,
B. Hahn, B. Korber, P. A. Marx, F. E. McCutchan, J. W.
Mellors, and S. Wolinsky. HIV sequence compendium.
Los Alamos, NM: Theoretical Biology and Biophysics
Group, Los Alamos National Laboratory. pp. 223. Retrieved 2010-09-19 Missing or empty |title= (help)
[3] Donald G. McNeil, Jr. (September 16, 2010). Precursor
to H.I.V. Was in Monkeys for Millennia. New York
Times. Retrieved 2010-09-17. In a discovery that sheds
new light on the history of AIDS, scientists have found evidence that the ancestor to the virus that causes the disease
has been in monkeys and apes for at least 32,000 years
not just a few hundred years, as had been previously
thought. ... That means humans have presumably been
exposed many times to S.I.V., the simian immunodeciency virus, because people have been hunting monkeys
for millenniums, risking infection every time they butcher
one for food.
[4] Worobey, Michael; Telfer, Paul; Souquire, Sandrine; Hunter, Meredith; Coleman, Clint A.;
Metzger, Michael J.; Reed, Patricia; Makuwa,
Maria; Hearn, Gail (2010).
Island Biogeography Reveals the Deep History of SIV.
Science
Bibcode:2010Sci...329.1487W.
329 (5998): 1487.
doi:10.1126/science.1193550. PMID 20847261..
[5] Kestler, H.; Kodama, T.; Ringler, D.; Marthas, M.; Pedersen, N.; Lackner, A.; Regier, D.; Sehgal, P.; Daniel,
M.; King, N.; Et, A. (1990). Induction of AIDS in
rhesus monkeys by molecularly cloned simian immunodeciency virus. Science 248 (4959): 11091112.
doi:10.1126/science.2160735. PMID 2160735.
[6] Letvin, N.; Eaton, K.; Aldrich, W.; Sehgal, P.;
Blake, B.; Schlossman, S.; King, N.; Hunt, R. (1983).
Acquired immunodeciency syndrome in a colony
of macaque monkeys. Proceedings of the National
Academy of Sciences of the United States of America
80 (9): 27182722. Bibcode:1983PNAS...80.2718L.
doi:10.1073/pnas.80.9.2718. PMC 393899. PMID
6221343.
[7] Daniel, M. D.; Letvin, N. L.; King, N. W.; Kannagi,
M.; Sehgal, P. K.; Hunt, R. D.; Kanki, P. J.; Essex, M.; Desrosiers, R. C. (1985). Isolation of T-cell
tropic HTLV-III-like retrovirus from macaques. Science
228 (4704): 12011204. Bibcode:1985Sci...228.1201D.
doi:10.1126/science.3159089. PMID 3159089.
[8] King, N. W.; Hunt, R. D.; Letvin, N. L. (1983).
Histopathologic changes in macaques with an acquired
immunodeciency syndrome (AIDS)". The American
journal of pathology 113 (3): 382388. PMC 1916356.
PMID 6316791.
[9] e., L.; Srinivasan, P.; m., J. (2012). Simian-Human
Immunodeciency Viruses and Their Impact on NonHuman Primate Models for AIDS. Immunodeciency.
doi:10.5772/53556. ISBN 978-953-51-0791-0.
[10] Chimpanzees Do Die From Simian AIDS, Study Finds by
Lawrence K. Altman Chimpanzees Do Die from Simian
AIDS, Study Finds
[11] Jonathan L. Heeney; Angus G. Dalgleish; Robin A.
Weiss (July 2006). Origins of HIV and the evolution of resistance to AIDS (PDF). Science 313
Bibcode:2006Sci...313..462H.
(5786):
462466.
doi:10.1126/science.1123016. PMID 16873637.
[12] ICTV database entry: 61.0.6.5.003
[13] McNeil Jr, Donald (17 September 2010). Precursor to
H.I.V. Was in Monkeys for Millenniums. The New York
Times. Retrieved 17 September 2010.
11
Chapter 4
HIV
This article is about the virus. For the disease caused Many species are infected by lentiviruses, which are charby the virus, see HIV/AIDS. For other uses, see HIV acteristically responsible for long-duration illnesses with
(disambiguation).
a long incubation period.[10] Lentiviruses are transmitted as single-stranded, positive-sense, enveloped RNA
viruses. Upon entry into the target cell, the viral RNA
AIDS virus redirects here. For the computer virus, see
genome is converted (reverse transcribed) into doubleAIDS (computer virus).
stranded DNA by a virally encoded reverse transcriptase
that is transported along with the viral genome in the virus
The human immunodeciency virus (HIV) is a particle. The resulting viral DNA is then imported into
lentivirus (a subgroup of retrovirus) that causes HIV the cell nucleus and integrated into the cellular DNA by a
infection and acquired immunodeciency syndrome virally encoded integrase and host co-factors.[11] Once in(AIDS).[1][2] AIDS is a condition in humans in which tegrated, the virus may become latent, allowing the virus
progressive failure of the immune system allows life- and its host cell to avoid detection by the immune systhreatening opportunistic infections and cancers to thrive. tem. Alternatively, the virus may be transcribed, producWithout treatment, average survival time after infection ing new RNA genomes and viral proteins that are packwith HIV is estimated to be 9 to 11 years, depending aged and released from the cell as new virus particles that
on the HIV subtype.[3] Infection with HIV occurs by the begin the replication cycle anew.
transfer of blood, semen, vaginal uid, pre-ejaculate, or
breast milk. Within these bodily uids, HIV is present as Two types of HIV have been characterized: HIV-1 and
both free virus particles and virus within infected immune HIV-2. HIV-1 is the virus that was initially discovered
and termed both LAV and HTLV-III. It is more virulent,
cells.
more infective,[12] and is the cause of the majority of HIV
HIV infects vital cells in the human immune system infections globally. The lower infectivity of HIV-2 comsuch as helper T cells (specically CD4+ T cells), pared to HIV-1 implies that fewer of those exposed to
macrophages, and dendritic cells.[4] HIV infection leads HIV-2 will be infected per exposure. Because of its relto low levels of CD4+ T cells through a number of atively poor capacity for transmission, HIV-2 is largely
mechanisms, including pyroptosis of abortively infected conned to West Africa.[13]
T cells,[5] apoptosis of uninfected bystander cells,[6] direct viral killing of infected cells, and killing of infected
CD4+ T cells by CD8 cytotoxic lymphocytes that recog- 4.1.2 Structure and genome
nize infected cells.[7] When CD4+ T cell numbers decline
below a critical level, cell-mediated immunity is lost, and Main article: Structure and genome of HIV
the body becomes progressively more susceptible to op- HIV is dierent in structure from other retroviruses. It
is roughly spherical[14] with a diameter of about 120 nm,
portunistic infections.
around 60 times smaller than a red blood cell, yet large
for a virus.[15] It is composed of two copies of positive
single-stranded RNA that codes for the viruss nine genes
4.1 Virology
enclosed by a conical capsid composed of 2,000 copies
of the viral protein p24.[16] The single-stranded RNA is
4.1.1 Classication
tightly bound to nucleocapsid proteins, p7, and enzymes
needed for the development of the virion such as reverse
See also: Subtypes of HIV
transcriptase, proteases, ribonuclease and integrase. A
matrix composed of the viral protein p17 surrounds the
[16]
[8]
HIV is a member of the genus Lentivirus,
part capsid ensuring the integrity of the virion particle.
of the family Retroviridae.[9] Lentiviruses have many This is, in turn, surrounded by the viral envelope, that
morphologies and biological properties in common. is composed of the lipid bilayer taken from the mem12
4.1. VIROLOGY
13
The RNA genome consists of at least seven structural
landmarks (LTR, TAR, RRE, PE, SLIP, CRS, and INS),
and nine genes (gag, pol, and env, tat, rev, nef, vif, vpr,
vpu, and sometimes a tenth tev, which is a fusion of tat
env and rev), encoding 19 proteins. Three of these genes,
gag, pol, and env, contain information needed to make the
structural proteins for new virus particles.[16] For example, env codes for a protein called gp160 that is broken
down by a cellular protease to form gp120 and gp41. The
six remaining genes, tat, rev, nef, vif, vpr, and vpu (or vpx
in the case of HIV-2), are regulatory genes for proteins
that control the ability of HIV to infect cells, produce new
copies of virus (replicate), or cause disease.[16]
Macrophage (M-tropic) strains of HIV-1, or nonsyncytia-inducing strains (NSI; now called R5 viruses[27]
) use the -chemokine receptor CCR5 for entry and
are, thus, able to replicate in macrophages and CD4+ T
cells.[28] This CCR5 coreceptor is used by almost all primary HIV-1 isolates regardless of viral genetic subtype.
Indeed, macrophages play a key role in several critical
14
CHAPTER 4. HIV
HIV from binding to this coreceptor, reducing its ability
to infect target cells.
Sexual intercourse is the major mode of HIV transmission. Both X4 and R5 HIV are present in the seminal
uid, which is passed from a male to his sexual partner. The virions can then infect numerous cellular targets and disseminate into the whole organism. However,
a selection process leads to a predominant transmission of
the R5 virus through this pathway.[33][34][35] How this selective process works is still under investigation, but one
model is that spermatozoa may selectively carry R5 HIV
as they possess both CCR3 and CCR5 but not CXCR4
on their surface[36] and that genital epithelial cells preferentially sequester X4 virus.[37] In patients infected with
subtype B HIV-1, there is often a co-receptor switch in
late-stage disease and T-tropic variants appear that can
infect a variety of T cells through CXCR4.[38] These variants then replicate more aggressively with heightened virulence that causes rapid T cell depletion, immune system
collapse, and opportunistic infections that mark the advent of AIDS.[39] Thus, during the course of infection,
viral adaptation to the use of CXCR4 instead of CCR5
may be a key step in the progression to AIDS. A number
of studies with subtype B-infected individuals have determined that between 40 and 50 percent of AIDS patients
can harbour viruses of the SI and, it is presumed, the X4
phenotypes.[40][41]
HIV-2 is much less pathogenic than HIV-1 and is restricted in its worldwide distribution. The adoption
of accessory genes by HIV-2 and its more promiscuous pattern of coreceptor usage (including CD4independence) may assist the virus in its adaptation
to avoid innate restriction factors present in host cells.
Adaptation to use normal cellular machinery to enable
transmission and productive infection has also aided the
establishment of HIV-2 replication in humans. A survival strategy for any infectious agent is not to kill its host
but ultimately become a commensal organism. Having
achieved a low pathogenicity, over time, variants more
successful at transmission will be selected.[42]
4.1. VIROLOGY
15
to play an important role by transmitting HIV to T-cells
when the virus is captured in the mucosa by DCs.[46] The
presence of FEZ-1, which occurs naturally in neurons, is
believed to prevent the infection of cells by HIV.[47]
HIV
2.
3.
gp41
gp120
CD4
CD4
gp120
CCR5
HIV
gp41
CD4
Cellular membrane
CD4+ T-Cell
CD4+ T-Cell
HIV
4.
HIV
gp41
gp41
gp120
CCR 5
CD4+ T-Cell
CCR5
CD4+ T-Cell
Clathrin-dependent endocytosis
HIV-1 entry, as well as entry of many other retroviruses, has long been believed to occur exclusively at
the plasma membrane. More recently, however, productive infection by pH-independent, clathrin-dependent
endocytosis of HIV-1 has also been reported and was recently suggested to constitute the only route of productive
entry.[48][49][50][51][52]
16
CHAPTER 4. HIV
arate progenitor parental viruses of diering genetic constitution. It is unknown how often such mixed packaging
occurs under natural conditions.[62]
Recombination
Two RNA genomes are encapsidated in each HIV-1 particle (see Structure and genome of HIV). Upon infection and replication catalyzed by reverse transcriptase, recombination between the two genomes can occur.[59][60]
Recombination occurs as the single-strand (+)RNA
genomes are reverse transcribed to form DNA. During
reverse transcription the nascent DNA can switch multiple times between the two copies of the viral RNA. This
form of recombination is known as copy-choice. Recombination events may occur throughout the genome. From
2 to 20 events per genome may occur at each replication cycle, and these events can rapidly shue the genetic
information that is transmitted from parental to progeny
genomes.[60]
Viral recombination produces genetic variation that likely
contributes to the evolution of resistance to anti-retroviral
therapy.[61] Recombination may also contribute, in principle, to overcoming the immune defenses of the host.
Yet, for the adaptive advantages of genetic variation to HIV assembling on the surface of an infected macrophage.
be realized, the two viral genomes packaged in individual infecting virus particles need to have arisen from sep- The nal step of the viral cycle, assembly of new HIV-
4.1. VIROLOGY
17
4.1.5
CHAPTER 4. HIV
CD4+ Lymphocyte Count (cells/mm 3 )
18
Three groups of HIV-1 have been identied on the basis of dierences in the envelope (env) region: M, N,
and O.[84] Group M is the most prevalent and is subdivided into eight subtypes (or clades), based on the whole
genome, which are geographically distinct.[85] The most
prevalent are subtypes B (found mainly in North America
and Europe), A and D (found mainly in Africa), and C
(found mainly in Africa and Asia); these subtypes form
branches in the phylogenetic tree representing the lineage of the M group of HIV-1. Coinfection with distinct subtypes gives rise to circulating recombinant forms
(CRFs). In 2000, the last year in which an analysis of
global subtype prevalence was made, 47.2% of infections
worldwide were of subtype C, 26.7% were of subtype
A/CRF02_AG, 12.3% were of subtype B, 5.3% were of
subtype D, 3.2% were of CRF_AE, and the remaining
5.3% were composed of other subtypes and CRFs.[86]
Most HIV-1 research is focused on subtype B; few laboratories focus on the other subtypes.[87] The existence of a
fourth group, P, has been hypothesised based on a virus
isolated in 2009.[88] The strain is apparently derived from
gorilla SIV (SIVgor), rst isolated from western lowland
gorillas in 2006.[88]
1200
Symptoms of
AIDS
Primary
infection
10 7
Death
1100
1000
Opportunistic
diseases
Clinical latency
900
10 6
800
10 5
Constitutional
symptoms
700
600
500
10 4
400
300
10 3
200
100
0
12
10
11
10 2
HIV-1 testing is initially by an enzyme-linked immunosorbent assay (ELISA) to detect antibodies to HIV1. Specimens with a nonreactive result from the initial
ELISA are considered HIV-negative unless new exposure
to an infected partner or partner of unknown HIV status
has occurred. Specimens with a reactive ELISA result are
retested in duplicate.[92] If the result of either duplicate
test is reactive, the specimen is reported as repeatedly
reactive and undergoes conrmatory testing with a more
specic supplemental test (e.g., Western blot or, less commonly, an immunouorescence assay (IFA)). Only specimens that are repeatedly reactive by ELISA and positive by IFA or reactive by Western blot are considered
HIV-positive and indicative of HIV infection. Specimens
that are repeatedly ELISA-reactive occasionally provide
an indeterminate Western blot result, which may be either an incomplete antibody response to HIV in an inor nonspecic reactions in an uninfected
HIV-2s closest relative is SIVsm, a strain of SIV found in fected person
[93]
person.
Sooty Mangabees. Since HIV-1 is derived from SIVcpz,
and HIV-2 from SIVsm, the genetic sequence of HIV-2
is only partially homologous to HIV-1 and more closely
resembles that of SIVsm.[89]
4.2 Diagnosis
Main article: HIV test
Many HIV-positive people are unaware that they are infected with the virus.[90] For example, in 2001 less than
1% of the sexually active urban population in Africa
had been tested, and this proportion is even lower in rural populations.[90] Furthermore, in 2001 only 0.5% of
pregnant women attending urban health facilities were
counselled, tested or receive their test results.[90] Again,
this proportion is even lower in rural health facilities.[90]
Since donors may therefore be unaware of their infection, donor blood and blood products used in medicine
and medical research are routinely screened for HIV.[91]
4.4. HISTORY
Mozambique (4.061%)
Zimbabwe (3.49%)
Cameroon (3.09%)
Indonesia (3.04%)
Kenya (2.98%)
Uganda (2.97%)
Malawi (2.94%)
DR Congo (2.17%)
Ethiopia (2.11%)
Other (29.21%)
19
fundamental research about the nature of HIV as an infectious agent and AIDS as the disease caused by HIV.
Many governments and research institutions participate
in HIV/AIDS research. This research includes behavioral health interventions, such as research into sex education, and drug development, such as research into
microbicides for sexually transmitted diseases, HIV vaccines, and antiretroviral drugs. Other medical research
areas include the topics of pre-exposure prophylaxis,
post-exposure prophylaxis, circumcision and HIV, and
accelerated aging eects.
4.3 Research
20
CHAPTER 4. HIV
Left to right: the African green monkey source of SIV, the sooty
mangabey source of HIV-2, and the chimpanzee source of HIV-1
There is evidence that humans who participate in with symptoms in 1966 died in 1969.[127]
bushmeat activities, either as hunters or as bushmeat vendors, commonly acquire SIV.[120] However, SIV is a weak
virus, and it is typically suppressed by the human immune 4.5 See also
system within weeks of infection. It is thought that several transmissions of the virus from individual to individ World AIDS Day
ual in quick succession are necessary to allow it enough
HIV/AIDS denialism
time to mutate into HIV.[121] Furthermore, due to its rela-
4.6. REFERENCES
21
Antiviral drug
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26
CHAPTER 4. HIV
Chapter 5
History of HIV/AIDS
5.1 Transmission
from
humans to humans
non-
27
28
There are six additional known HIV-2 groups, each having been found in just one person. They all seem to derive
from independent transmissions from sooty mangabeys to
humans. Groups C and D have been found in two people from Liberia, groups E and F have been discovered in
two people from Sierra Leone, and groups G and H have
been detected in two people from the Ivory Coast. These
HIV-2 strains are probably dead-end infections, and each
of them is most closely related to SIVsmm strains from
types of apes, shown to carry the SIV virus, are dierent in South America. The primary point of entry, according to researchers, is somewhere in the jungles of
Argentina or Brazil.[28] An SIV strain, closely related to
HIV, was interspersed within a certain clade of primates.
This suggests that the zoonotic transmission of the virus
may have happened in this area.[28] Continual emigration
between countries escalated the transmission of the virus.
Other scientists believe that the HIV-1C strain circulated
evidence
of
current or past SIV infection
to determine the initial date of transmission, which is es[20]
was
2.3%
among
the
general
population of Cameroon,
timated to be around 1915-1931.
7.8% in villages where bushmeat is hunted or used, and
17.1% in the most exposed people of these villages.[26]
How the SIV virus would have transformed into HIV af5.1.2 HIV-2 from sooty mangabeys to hu- ter infection of the hunter or bushmeat handler from the
mans
ape/monkey is still a matter of debate, although natural
selection would favor any viruses capable of adjusting so
Similar research has been undertaken with SIV strains that they could infect and reproduce in the T cells of a
collected from several wild sooty mangabey (Cercocebus human host.
atys atys) (SIVsmm) populations of the West African na- A study published in 2009 also discussed that bushmeat
tions of Sierra Leone, Liberia, and Ivory Coast. The re- in other parts of the world, such as Argentina, may be
sulting phylogenetic analyses show that the viruses most a possible location for where the disease originated.[27]
closely related to the two strains of HIV-2 that spread HIV-1C, a subtype of HIV, was theorized to have its oriconsiderably in humans (HIV-2 groups A and B) are the gins circulating among South America.[28] The consumpSIVsmm found in the sooty mangabeys of the Tai forest, tion of bushmeat is also the most probable cause for the
in western Ivory Coast.[3]
emergence of HIV-1C in South America. However, the
5.2. EMERGENCE
29
in South America at around the same time that the HIV1C strain was introduced in Africa.[28] Very little research
has been done on this theory because it is fairly young.
However, promising evidence indicates that there may be
some validity to this hypothesis.
5.2.2
It was proposed by Beatrice Hahn, Paul Sharp, and colleagues that "[the epidemic emergence of HIV] most
likely reects changes in population structure and behaviour in Africa during the 20th century and perhaps
medical interventions that provided the opportunity for
rapid human-to-human spread of the virus.[8] After the
Scramble for Africa started in the 1880s, European colonial powers established cities, towns, and other colonial
stations. A largely masculine labor force was hastily recruited to work in uvial and sea ports, railways, other
infrastructures, and in plantations. This disrupted traditional tribal values, and favored sexual promiscuity. In
the nascent cities women felt relatively liberated from rural tribal rules[30] and many remained unmarried or divorced during long periods,[12][31] this being very rare in
African traditional societies.[32] This was accompanied
by unprecedented increase in peoples movements.
Several of the theories of HIV origin put forward (described below) attempt to explain the unresolved loose
ends described in the previous section. Most of them accept the (above described) established knowledge of the Michael Worobey and colleagues observed that the
30
Unsterile injections
Marx et al. reported experiments of cross-species transfer of SIV in captive monkeys (some of which made by
themselves), in which the use of serial passage helped to
adapt SIV to the new monkey species after passage by
three or four animals.[21]
5.2. EMERGENCE
probability of transmission after a needle reuse is something between 0.3% and 2%, and only a few people have
an acute SIV infection at any time), and so HIV emergence may have required the very high frequency of injections of the antibiotic era.[21]
31
32
Sousa et al. charts reveal that male circumcision frequencies were much lower in several cities of western and central Africa in the early 20th century than they are currently. The reason is that many ethnic groups not per-
33
SIVcpz infection do experience an increased mortality,
and also suer from a Human AIDS-like illness.[48] SIV
pathogenicity in wild animals could exist in other chimpanzee subspecies and other primate species as well, and
stay unrecognized by lack of relevant long term studies.
One of the main advantages of this theory is stressed by Main article: Timeline of early AIDS cases
the authors: It [the theory] also oers a conceptual simplicity because it proposes as causal factors for SIV adaptation to humans and initial spread the very same factors
that most promote the continued spread of HIV nowa- 5.4.1 1959: David Carr
days: promiscuous sex, particularly involving sex workers, GUD, and possibly lack of circumcision.[12]
David Carr was an apprentice printer (usually referred to,
mistakenly, as a sailor; Carr had served in the Navy between 1955 and 1957) from Manchester, England who
Iatrogenic and other theories
died August 31, 1959, and was for some time mistakenly
reported to have died from AIDS-dening opportunistic
Iatrogenic theories propose that medical interventions infections (ADOIs). Following the failure of his immune
were responsible for HIV origins. By proposing factors system, he succumbed to pneumonia. Doctors, baed by
that only appeared in Central and West Africa after the what he had died from, preserved 50 of his tissue samlate 19th century, they seek to explain why all HIV groups ples for inspection. In 1990, the tissues were found to be
also started after that.
HIV-positive. However, in 1992, a second test by AIDS
The theories centered on the role of parenteral risks, researcher David Ho found that the strain of HIV present
such as unsterile injections, transfusions,[21][33][40][41] or in the tissues was similar to those found in 1990 rather
smallpox vaccinations[33] are accepted as plausible by than an earlier strain (which would have mutated considmost scientists of the eld, and were already reviewed erably over the course of 30 years). He concluded that the
DNA samples provided actually came from a 1990 AIDS
above.
patient. Upon retesting David Carrs tissues, he found no
Discredited HIV/AIDS origins theories include several
sign of the virus.[49][50][51]
iatrogenic theories, such as Edward Hooper's 1999 claim
that early oral polio vaccines, contaminated with a chimpanzee virus, caused the Central African outbreak.[46]
5.4.2 1959: Congolese man
One of the earliest documented HIV-1 infections was discovered in a preserved blood sample taken in 1959 from
a man from Lopoldville in the Belgian Congo.[52] However, it is unknown whether this anonymous person ever
developed AIDS and died of its complications.[52]
In addition, a long-term survey of chimpanzees naturally In May 1969 16-year-old African-American Robert Rayinfected with SIVcpz in Gombe, Tanzania found that, ford died at the St. Louis City Hospital from Kaposis sarcontrary to the previous paradigm, chimpanzees with coma. In 1987 researchers at Tulane University School
34
of Medicine detected a virus closely related or identical to[53] HIV-1 in his preserved blood and tissues. The
doctors who worked on his case at the time suspected he
was a prostitute or the victim of sexual abuse, though
the patient did not discuss his sexual history with them
in detail.[53][54][55][56][57]
5.4.5
From 1972 to 1973, researchers drew blood from 75 children in Uganda to serve as controls for a study of Burkitts
lymphoma. In 1985, retroactive testing of the frozen
blood serum indicated that antibodies to a virus related
to HIV were present in 50 of the children.[60]
A Canadian airline steward named Gatan Dugas was referred to as Patient 0 in an early AIDS study by Dr.
William Darrow of the Centers for Disease Control. Because of this, many people had considered Dugas to be
responsible for bringing HIV to North America. This is
not accurate, however, as HIV had spread long before
Dugas began his career. This rumor may have started
with Randy Shilts' 1987 book And the Band Played On
(and the 1993 movie based on it, in which Dugas is referred to as AIDS' Patient Zero), but neither the book
nor the movie states that he had been the rst to bring the
virus to North America. He was called Patient Zero because at least 40 of the 248 people known to be infected
by HIV in 1983 had had sex with him, or with someone
who had sexual intercourse with him.
5.4.7
5.4.6
5.6. CLASSIFICATION
35
5.6 Classication
Since June 5, 1981, many denitions have been develIn May 1983, doctors from Dr. Luc Montagnier's team at oped for epidemiological surveillance such as the Bangui
the Pasteur Institute in France reported that they had iso- denition and the 1994 expanded World Health Organilated a new retrovirus from lymphoid ganglions that they zation AIDS case denition.
believed was the cause of AIDS.[76] The virus was later
named lymphadenopathy-associated virus (LAV) and a
sample was sent to the U.S. Centers for Disease Control,
which was later passed to the National Cancer Institute 5.7 Genetic studies
(NCI).[76][77]
According to a study published in the Proceedings of the
National Academy of Sciences in 2008, a team led by
5.5.2 May 1984: HTLV-III
Robert Shafer at Stanford University School of Medicine
has discovered that the Gray Mouse Lemur has an
In May 1984 a team led by Robert Gallo of the United endogenous lentivirus (the genus to which HIV belongs)
States conrmed the discovery of the virus, but they re- in its genetic makeup. This suggests that lentiviruses have
named it human T lymphotropic virus type III (HTLV- existed for at least 14 million years, much longer than
III).[78]
the currently known existence of HIV. In addition, the
time frame falls into place when Madagascar was still
yet connected to what is now the African continent; the
5.5.3 January 1985: both found to be the said lemurs later developed immunity to the virus strain
and survived an era when the lentivirus was widespread
same
among other mammalia. The study is being hailed as cruIn January 1985, a number of more-detailed reports cial, because it lls the blanks in the origin of the virus,
be important in the
were published concerning LAV and HTLV-III, and by as well as in its evolution, and may[85][86]
development
of
new
antiviral
drugs.
March it was clear that the viruses were the same, were
from the same source, and were the etiological agent of In 2010, researchers reported that SIV had infected monAIDS.[79][80]
keys in Bioko for at least 32,000 years. Previous to this
time, it was thought that SIV infection in monkeys had
happened over the past few hundred years.[87] Scientists
estimated that it would take a similar amount of time be5.5.4 May 1986: the name HIV
fore humans adapted naturally to HIV infection in the way
In May 1986, the International Committee on Taxonomy monkeys in Africa have adapted to SIV and not suer any
[88]
of Viruses ruled that both names should be dropped and harm from the infection.
a new name, HIV (Human Immunodeciency Virus), be
used.[81]
Nobel
36
or an accident. These hypotheses have been rejected by
scientic consensus.
5.10 Notes
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Bibollet-Ruche F, Fruteau C, No R, Peeters M, Brookeld JF, Shaw GM, Sharp PM, Hahn BH (2005).
Simian Immunodeciency Virus Infection in FreeRanging Sooty Mangabeys (Cercocebus atys atys) from
the Tai Forest, Cote d'Ivoire: Implications for the
Origin of Epidemic Human Immunodeciency Virus
Type 2.
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1211554. PMID 16160179.
[4] Keele BF, Van Heuverswyn F, Li Y, Bailes E, Takehisa J, Santiago ML, Bibollet-Ruche F, Chen Y, Wain
LV, Liegeois F, Loul S, Ngole EM, Bienvenue Y,
Delaporte E, Brookeld JF, Sharp PM, Shaw GM,
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doi:10.1126/science.1126531. PMC 2442710. PMID
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[5] HIVs ancestry traced to wild chimps in Cameroon.
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BF, Liu W, Loul S, Butel C, Liegeois F, Bienvenue
Y, Ngolle EM, Sharp PM, Shaw GM, Delaporte E,
Hahn BH, Peeters M (2006). Human immunodeciency viruses: SIV infection in wild gorillas. Nature 444 (7116): 164. Bibcode:2006Natur.444..164V.
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Santiago MO, Hahn BH (2001). The origins of acquired immune deciency syndrome viruses: where
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Michael SF, Cummins LB, Arthur LO, Peeters M, Shaw
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AM (2004).
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[31] Gondola, Charles Didier (1996). Villes miroirs: migrations et identits urbaines Kinshasa et Brazzaville, 1930
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[46] Ramsay S (2001).
Cold water downstream from
The River.
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Bibollet-Ruche F, Mller-Trutwin MC, Novembre FJ,
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Silvestri G, Sharp PM, Hahn BH, Kirchho F (2006).
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TM, Schumacher-Stankey J, Wroblewski E, Mosser
A, Raphael J, Kamenya S, Lonsdorf EV, Travis DA,
Mlengeya T, Kinsel MJ, Else JG, Silvestri G, Goodall
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pneumonia among homosexual male residents of Los Angeles and Orange Counties, California. MMWR Morb.
5.10. NOTES
39
Chapter 6
HIV/AIDS denialism
discourages HIV-positive people from using proven
treatments.[2][8][10][11][12][13] Public health researchers
have attributed 330,000 to 340,000 AIDS deaths, along
with 171,000 other HIV infections and 35,000 infant HIV
infections, to the South African governments former embrace of HIV/AIDS denialism.[14][15] The interrupted use
of antiviral treatments is also a major global concern as it
potentially increases the likelihood of the emergence of
antiviral resistance strains of the virus.[16]
6.1 History
In 1983, a group of scientists and doctors at the Pasteur
Institute in France, led by Luc Montagnier, discovered a new virus in a patient with signs and symptoms that often preceded AIDS.[17] They named the
virus lymphadenopathy-associated virus, or LAV, and
HIV/AIDS denialism is the belief, contradicted by con- sent samples to Robert Gallo's team in the United States.
clusive medical and scientic evidence,[1][2] that human Their ndings were peer reviewed and slated for publicaimmunodeciency virus (HIV) does not cause acquired tion in Science.
immune deciency syndrome (AIDS).[3] Some denialists At a 23 April 1984 press conference in Washington, D.C.,
reject the existence of HIV, while others accept that HIV Margaret Heckler, Secretary of Health and Human Serexists but say that it is a harmless passenger virus and vices, announced that Gallo and his co-workers had disnot the cause of AIDS. Insofar as denialists acknowledge covered a virus that is the probable cause of AIDS.
AIDS as a real disease, they attribute it to some combina- This virus was initially named HTLV-III.[18] That same
tion of sexual behavior, recreational drugs, malnutrition, year, Casper Schmidt responded to Gallos papers with
poor sanitation, haemophilia, or the eects of the drugs The Group-Fantasy Origins of AIDS, Journal of Psyused to treat HIV infection.[4][5]
chohistory.[19] Schmidt posited that AIDS was not an acThe scientic consensus is that the evidence showing tual disease, but rather an example of "epidemic hysteria"
HIV to be the cause of AIDS is conclusive[1][2] and in which groups of people are subconsciously acting out
that HIV/AIDS denialist claims are pseudoscience based social conicts. Schmidt compared AIDS to documented
on conspiracy theories,[6] faulty reasoning, cherry pick- cases of epidemic hysteria in the past which were mis(Schmidt himself would
ing, and misrepresentation of mainly outdated scientic takenly thought to be infectious.
[20][21]
later
die
of
AIDS
in
1994.)
[1][2][7]
data.
With the rejection of these arguments by
Electron micrograph of the human immunodeciency virus.
HIV/AIDS denialism disputes the existence of HIV or its role in
causing AIDS.
the scientic community, HIV/AIDS denialist material is In 1986, the viruses discovered by Montagnier and Gallo,
now targeted at less scientically sophisticated audiences found to be genetically indistinguishable, were renamed
HIV.[22]
and spread mainly through the Internet.[8][9]
Despite its lack of scientic acceptance, HIV/AIDS denialism has had a signicant political impact, especially in South Africa under the presidency of Thabo
Mbeki. Scientists and physicians have raised alarm
at the human cost of HIV/AIDS denialism, which
40
6.1. HISTORY
In 1988, a panel of the Institute of Medicine of the U.S.
National Academy of Sciences found that the evidence
that HIV causes AIDS is scientically conclusive.[1]
That same year, Science published Blattner, Gallo, and
Temins HIV causes AIDS,[24] and Duesbergs HIV
is not the cause of AIDS.[25] Also that same year, the
Perth Group, a group of denialists based in Perth, Western Australia led by Eleni Papadopulos-Eleopulos, published in the non-peer-reviewed journal Medical Hypotheses their rst article questioning aspects of HIV/AIDS
research,[26] arguing that there was no compelling reason for preferring the viral hypothesis of AIDS to one
based on the activity of oxidising agents.
In 1989, Duesberg exercised his right, as a member of
the National Academy of Sciences, to bypass the peer review process and publish his arguments in Proceedings
of the National Academy of Sciences of the United States
of America (PNAS) unreviewed. The editor of PNAS initially resisted, but ultimately allowed Duesberg to publish,
saying, If you wish to make these unsupported, vague,
and prejudicial statements in print, so be it. But I cannot see how this would be convincing to any scientically
trained reader.[27]
41
claimed to have been drawn up by the Pasteur Institute
in 1973.[35] The challenge was later dismissed by various scientists, including Duesberg, asserting that HIV undoubtedly exists.[35] Stefan Lanka argued in the same year
that HIV does not exist.[36]
In 1996, the British Medical Journal published Response: arguments contradict the foreign proteinzidovudine hypothesis[37] as a response to a petition by
Duesberg: In 1991 Duesberg challenged researchers
We and Darby et al. have provided that evidence. The
paper argued that Duesberg was wrong regarding the
cause of AIDS in haemophiliacs. In 1997, The Perth
Group questioned the existence of HIV, and speculated
that the production of antibodies recognizing HIV proteins can be caused by allogenic stimuli and autoimmune
disorders.[38][39] They continued to repeat this speculation through at least 2006.[40]
42
In 2008, University of Cape Town researcher Nicoli Nattrass, and later that year a group of Harvard scientists led
by Zimbabwean physician Pride Chigwedere each independently estimated that Thabo Mbekis denialist policies led to the early deaths of more than 330,000 South
Africans.[14][15] Barbara Hogan, the health minister appointed by Mbekis successor, voiced shame over the
studies ndings and stated: The era of denialism is over
completely in South Africa.[48]
43
the political aspects of the HIV/AIDS denialism movement, Sociology professor Steven Epstein wrote in Impure Science that "... the appeal of Duesbergs views to
conservativescertainly including those with little sympathy for the gay movementcannot be denied.[70] The
blog LewRockwell.com has also published articles supportive of HIV/AIDS denialism.[76]
44
45
poppers, and that the government had conspired to hide protected anal sex and poppers on homosexual men, an
the truth.[87] Lauritsens The AIDS War was published in argument which does not account for AIDS in drug-free
1993.[88]
heterosexual women who deny participating in anal sex.
In this case, HIV/AIDS denialists claim the women are
having anal sex but refuse to disclose it. In haemophiliac
North American children who contracted AIDS from
In the scientic literature
blood transfusions, the haemophilia itself or its treatment
The publication of Duesbergs rst AIDS paper in 1987 is claimed to cause AIDS. In Africa, AIDS is blamed on
provided visibility for denialist claims. Shortly after- poor nutrition and sanitation due to poverty. For wealthy
wards, the journal Science reported that Duesbergs re- populations in South Africa with adequate nutrition and
marks had won him a large amount of media attention, sanitation, it is claimed that the antiretroviral drugs used
particularly in the gay press where he is something of a to treat AIDS cause the condition. In each case, the most
hero.[89] However, Duesbergs support in the gay com- parsimonious explanation and uniting factor HIV posimunity dried up as he made a series of statements per- tive status is ignored, as are the thousands of studies that
conclusion that AIDS is caused
ceived as homophobic; in an interview with the Village converge on the common
[5]
by
HIV
infection.
Voice in 1988, Duesberg stated his belief that the AIDS
epidemic was caused by a lifestyle that was criminal Haemophilia is considered the best test of the HIV-AIDS
twenty years ago.[90]
hypothesis by both denialists and AIDS researchers.
In the following few years, others became skeptical of the While Duesberg claims AIDS in haemophiliacs is caused
HIV theory as researchers initially failed to produce an by contaminated clotting factors and HIV is a harmless
eective treatment or vaccine for AIDS.[91] Journalists passenger virus, this result is contradicted by large studsuch as Neville Hodgkinson and Celia Farber regularly ies on haemophiliac patients who received contaminated
promoted denialist ideas in the American and British me- blood. A comparison of groups receiving high, medium
dia; several television documentaries were also produced and low levels of contaminated clotting factors found the
to increase awareness of the alternative viewpoint.[92] death rates diered signicantly depending on HIV staIn 19921993, The Sunday Times, where Hodgkinson tus. Of 396 HIV positive haemophiliacs followed beserved as scientic editor, ran a series of articles argu- tween 1985 and 1993, 153 died. The comparative ging that the AIDS epidemic in Africa was a myth. These ure for the HIV negative group was one out of 66, dearticles stressed Duesbergs claims and argued that antivi- spite comparable doses of contaminated clotting factors.
ral therapy was ineective, HIV testing unreliable, and A comparison of individuals receiving blood donations
that AIDS was not a threat to heterosexuals. The Sun- also supports the results; in 1994 there were 6888 indiday Times coverage was heavily criticized as slanted, mis- viduals with AIDS who had their HIV infection traced to
leading, and potentially dangerous; the scientic journal blood transfusions. Since the introduction of HIV testbe
Nature took the unusual step of printing a 1993 edito- ing, the number of individuals whose AIDS status can [4]
traced
to
blood
transfusions
was
only
29
(as
of
1994).
rial calling the papers coverage of HIV/AIDS seriously
mistaken, and probably disastrous.[93]
Finding diculty in publishing his arguments in the scientic literature, Duesberg exercised his right as a member of the National Academy of Sciences to publish in
Proceedings of the National Academy of Sciences of the
United States of America (PNAS) without going through
the peer review process. However, Duesbergs paper
raised a red ag at the journal and was submitted by
the editor for non-binding review. All of the reviewers found major aws in Duesbergs paper; the reviewer
specically chosen by Duesberg noted the presence of
misleading arguments, nonlogical statements, misrepresentations, and political overtones.[27] Ultimately,
the editor of PNAS acquiesced to publication,[94] writing
to Duesberg: If you wish to make these unsupported,
vague, and prejudicial statements in print, so be it. But I
cannot see how this would be convincing to any scientifically trained reader.[27]
HIV/AIDS denialists often resort to special pleading to
support their assertion, arguing for dierent causes of
AIDS in dierent locations and subpopulations. In North
America, AIDS is blamed on the health eects of un-
46
171,000 infections resulted from the Mbeki administrations policies, an outcome she refers to in the words of
[15]
In addition to elements of the popular and alternative Peter Mandelson as genocide by sloth.
press, AIDS denialist ideas are propagated largely via the
Internet.[96]
Durban Declaration
A 2007 article in PLoS Medicine noted:
In 2000, when the International AIDS Conference was
held in Durban, Mbeki convened a Presidential Advisory
Because these denialist assertions are
Panel containing a number of HIV/AIDS denialists, inmade in books and on the Internet rather than
cluding Duesberg and David Rasnick.[99] The Advisory
in the scientic literature, many scientists are
Panel meetings were closed to the general press; an ineither unaware of the existence of organized
vited reporter from the Village Voice wrote that Rasnick
denial groups, or believe they can safely ignore
advocated that HIV testing be legally banned and denied
them as the discredited fringe. And indeed,
that he had seen any evidence of an AIDS catastrophe
most of the HIV deniers arguments were
in South Africa, while Duesberg gave a presentation so
answered long ago by scientists. However,
removed from African medical reality that it left several
many members of the general public do not
local doctors shaking their heads.[47]
have the scientic background to critique the
assertions put forth by these groups, and not
In his address to the International AIDS Conference,
only accept them but continue to propagate
Mbeki reiterated his view that HIV was not wholly rethem.[8]
sponsible for AIDS, leading hundreds of delegates to
AIDS activists have expressed concern that denialist arguments about HIVs harmlessness may be responsible
for an upsurge in HIV infections. Denialist claims continue to exert a signicant inuence in some communities; a survey conducted at minority gay pride events in
four American cities in 2005 found that 33% of attendees
doubted that HIV caused AIDS.[97] According to Stephen
Thomas, director of the University of Pittsburgh Center
for Minority Health, people are focusing on the wrong
thing. They're focusing on conspiracies rather than protecting themselves, rather than getting tested and seeking
out appropriate care and treatment.[98]
6.4.2
47
6.6 Footnotes
[1] Confronting AIDS: Update 1988. Institute of Medicine
of the U.S. National Academy of Sciences. 1988. the
evidence that HIV causes AIDS is scientically conclusive.
[2] The Evidence that HIV Causes AIDS. National Institute of Allergy and Infectious Disease. 4 September 2009.
Retrieved 14 October 2009.
[3] Kalichman 2009, p. 205.
[4] Cohen, J. (1994).
Duesberg and critics agree:
hemophilia is the best test.
Science 266 (5191):
16451646.
Bibcode:1994Sci...266.1645C.
doi:10.1126/science.7992044. PMID 7992044.
[5] Kalichman 2009.
[6] Kalichman, Seth C. (1 January 2014). The Psychology
of AIDS Denialism. European Psychologist 19 (1): 13
22. doi:10.1027/1016-9040/a000175.
[7] Denying science. Nat. Med. 12 (4): 369. 2006.
doi:10.1038/nm0406-369. PMID 16598265. To support
their ideas, some AIDS denialists have also misappropriated a scientic review in Nature Medicine which opens
with this reasonable statement: Despite considerable advances in HIV science in the past 20 years, the reason why
HIV-1 infection is pathogenic is still debated.
[8] Smith, TC; Novella, SP (August 2007). HIV denial in the internet era. PLOS Medicine 4 (8): e256.
doi:10.1371/journal.pmed.0040256.
PMC 1949841.
PMID 17713982. Archived from the original on 6 May
2008.
[9] Steinberg, J (17 June 2009). AIDS denial: A lethal delusion. New Scientist 2713. Retrieved 14 October 2009.
[10] Cohen
(December
1994).
The
Duesberg
48
scientic prinDrugs.
2012.
6.6. FOOTNOTES
49
[57] Steinberg, J (23 June 2009). Five myths about HIV and
AIDS. New Scientist. Retrieved 4 February 2011.
[43] Gallo, R; Geen, N; Gonsalves, G; Jeerys, R; Kuritzkes, DR; Mirken, B; Moore, JP; Safrit, JT (25 March
2006). Errors in Celia Farbers March 2006 article in
Harpers Magazine (PDF). Treatment Action Campaign.
Archived (PDF) from the original on 16 June 2009. Retrieved 11 June 2009.
[44] Shadow of doubters. Brisbane Times. 5 May 2007.
Archived from the original on 27 April 2009. Retrieved
11 June 2009.
[45] Boy is healthy without drug for HIV, mother says. The
New York Times. 20 September 1998. Retrieved 11 June
2009.
[46] Harkavy, J (10 March 2006). Nikolas Emerson, 11; Case
led to legal ght over HIV. Boston Globe. Retrieved 11
June 2009.
[47] Schoofs, M (5 July 2000). Debating the obvious: Inside the South African governments controversial AIDS
panel. Village Voice. Retrieved 11 June 2009.
[48] Dugger, C (25 November 2008). Study cites toll of AIDS
policy in South Africa. The New York Times. Retrieved
17 December 2008.
[49] Turner, V (1999). E-Mail Correspondence Between Val
Turner and Robin Weiss. virusmyth.com.
[50] Duesberg, P (1989). Human immunodeciency virus
and acquired immunodeciency syndrome: Correlation but not causation. Proceedings of the National
Academy of Sciences of the United States of America 86 (3): 75564. Bibcode:1989PNAS...86..755D.
doi:10.1073/pnas.86.3.755.
PMC 286556.
PMID
2644642.
[51] 10 Scientic Reasons Why HIV Cannot Cause AIDS.
HealToronto.com. Retrieved 28 September 2006.
[52] Duesberg, P; Koehnlein, C; Rasnick, D (2003). The
chemical bases of the various AIDS epidemics: Recreational drugs, anti-viral chemotherapy and malnutriJournal of Biosciences 28 (4): 383412.
tion.
doi:10.1007/BF02705115. PMID 12799487.
[53] Basic Information about HIV and AIDS. Centers for
Disease Control. 11 August 2010. Retrieved 4 February
2011.
[54] O'Brien, SJ; Goedert, JJ (1996). HIV causes AIDS:
Kochs postulates fullled. Current Opinion in Immunology 8 (5): 6138. doi:10.1016/S0952-7915(96)80075-6.
PMID 8902385.
[55] HIV Science and Responsible Journalism (PDF). XVI
International AIDS Conference. 13 August 2006. Retrieved 17 December 2008.
50
51
[105] Manto again angers AIDS activists. AEGIS.com. Retrieved 20 September 2006.
[106] Nattrass, N. AIDS, science and governance (PDF). aidstruth.org. Archived from the original (PDF) on 23 June
2006.
6.7 References
Kalichman, Seth (2009). Denying AIDS: Conspiracy Theories, Pseudoscience, and Human Tragedy.
New York: Copernicus Books (Springer Science+Business Media). ISBN 9780387794754.
Chapter 7
Subtypes of HIV
One of the obstacles to treatment of the human immunodeciency virus is its high genetic variability.[1] HIV can
be divided into two major types, HIV type 1 (HIV-1) and
HIV type 2 (HIV-2). HIV-1 is related to viruses found in
chimpanzees and gorillas living in western Africa, while
HIV-2 viruses are related to viruses found in the endangered west African primate sooty mangabey.[2] HIV-1
viruses may be further divided into groups. The HIV-1
group M viruses predominate and are responsible for the
AIDS pandemic. Group M can be further subdivided into
subtypes based on genetic sequence data. Some of the
subtypes are known to be more virulent or are resistant
to dierent medications. Likewise, HIV-2 viruses are
thought to be less virulent and transmissible than HIV1 M group viruses, although HIV-2 is known to cause
AIDS.
7.1.1
HIV-1
These subtypes are sometimes further split into subsubtypes such as A1 and A2 or F1 and F2. In 2015, the
Group M
strain CRF19, a recombinant of subtype A, subtype D
and subtype G, with a subtype D protease, was found to
With 'M' for major, this is by far the most common type be strongly associated with rapid progression to AIDS in
of HIV, with more than 90% of HIV/AIDS cases deriv- Cuba.[8] This is not thought to be a complete or nal list,
ing from infection with HIV-1 group M. The M group is and further types are likely to be found.[9]
subdivided further into clades, called subtypes, that are
also given a letter. There are also circulating recombinant forms or CRFs derived from recombination be- Group N
tween viruses of dierent subtypes which are each given
a number. CRF12_BF, for example, is a recombination The 'N' stands for non-M, non-O. This group was disbetween subtypes B and F.
covered in 1998 and has only been seen in Cameroon.
As of 2006, only 10 Group N infections had been
Subtype A is common in West Africa.[4]
identied.[10]
52
53
which spread considerably in humans (HIV-2 groups A
and B) is the SIVsmm found in the sooty mangabeys of
the Tai forest, in western Ivory Coast.[18]
Group O
The O (Outlier) group is not usually seen outside of
West-central Africa. It is reportedly most common in
Cameroon, where a 1997 survey found that about 2% of
HIV-positive samples were from Group O.[11] The group
caused some concern because it could not be detected by
early versions of the HIV-1 test kits. More advanced HIV
tests have now been developed to detect both Group O
and Group N.[12]
Group P
In 2009, a newly analyzed HIV sequence was reported
to have greater similarity to a simian immunodeciency
virus recently discovered in wild gorillas (SIVgor) than
to SIVs from chimpanzees (SIVcpz). The virus had been
isolated from a Cameroonian woman residing in France
who was diagnosed with HIV-1 infection in 2004. The
scientists reporting this sequence placed it in a proposed
Group P pending the identication of further human
cases.[13][14][15]
7.1.2
HIV-2
There are six additional known HIV-2 groups, each having been found in just one person. They all seem to derive
from independent transmissions from sooty mangabeys to
humans. Groups C and D have been found in two people from Liberia, groups E and F have been discovered
in two people from Sierra Leone, and groups G and H
have been detected in two people from the Ivory Coast.
Each of these HIV-2 strains, for which humans are probably dead-end hosts, is most closely related to SIVsmm
strains from sooty mangabeys living in the same country
where the human infection was found.[18][19]
Diagnosis
HIV-2 diagnosis can be made when a patient has no
symptoms but positive blood work indicating the individual has HIV. The Multispot HIV-1/HIV-2 Rapid Test is
currently the only FDA approved method for such differentiation between the two viruses. Recommendations
for the screening and diagnosis of HIV has always been
to use enzyme immunoassays that detect HIV-1, HIV-1
group O, and HIV-2.[20] When screening the combination, if the test is positive followed by an indeterminate
HIV-1 western blot, a follow up test, such as amino acid
testing, must be performed to distinguish which infection
is present.[21] According to the NIH, a dierential diagnosis of HIV-2 should be considered when a person is of
West African descent or has had sexual contact or shared
needles with such a person. West Africa is at the highest
risk as it is the origin of the virus.
Treatments
HIV-2 has been found to be less pathogenic than HIV1. The mechanism of HIV-2 is not clearly dened, nor
the dierence from HIV-1, however the transmission
rate is much lower in HIV-2 than HIV-1. Both infections can lead to AIDS in aected individuals and both
can mutate to develop drug resistance.[20] Disease Monitoring in patients with HIV-2 includes clinical evaluation and CD4 cell counts, while treatment includes AntiRetroviral Therapy (ART), Nucleoside Reverse Transcriptase Inhibitors (NRTIs), Protease Inhibitors (PI),
and Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs) with the addition of CCR5 co-receptor antagonists and fusion inhibitors.[22] Choice of initial and/or
second-line therapy for HIV-2 has not yet been dened.
HIV-2 appears to be resistant to NNRTIs intrinsically,
but may be sensitive to NRTIs, though the mechanism is
poorly understood. Protease inhibitors have shown variable eect, while integrase inhibitors are also being evaluated. Combination regimens of the above listed therapies are being looked into as well, also showing variable eect depending on the types of therapies com-
54
Pregnancy
If a pregnant mother is exposed, screening is performed
as normal. If HIV-2 is present, a number of perinatal
ART drugs may be given as a prophylactic to lower the
risk of mother-to-child transmission. After the child is
born, a standard 6-week regimen of these prophylactics
should be initiated. Breast milk may also contain particles of HIV-2; therefore, breastfeeding is strictly advised
against.[21]
7.2 Evolution
The AIDS virus is evolving to a milder form but is an
awfully long way from no longer being deadly.[23]
7.2.1
7.4 References
[1] Robertson DL, Hahn BH, Sharp PM; Hahn; Sharp (March
1995). Recombination in AIDS viruses. J. Mol. Evol.
40 (3): 24959. doi:10.1007/BF00163230. PMID
7723052.
[2] Sharp, P. M.; Hahn, B. H. (2011). Origins of
HIV and the AIDS Pandemic (PDF). Cold Spring
Harbor Perspectives in Medicine 1 (1): a006841
doi:10.1101/cshperspect.a006841.
PMC
a006835.
3234451. PMID 22229120.
[3] Dhar, D. V., Amit, P., & Kumar, M. S. In-Silico Identication of New Genes in HIV-1 by ORF Prediction
Method. I. Res. J. Biological Sci., 1(7), 52-54(2012)
[4] Bobkov AF, Kazennova EV, Selimova LM; et al. (October 2004). Temporal trends in the HIV-1 epidemic in
Russia: predominance of subtype A. J. Med. Virol. 74
(2): 1916. doi:10.1002/jmv.20177. PMID 15332265.
[5] Goudsmit, Jaap. Viral Sex; The Nature of AIDS. Oxford
University Press. New York, New York, 1997. Pg. 51-58.
Retrieved May 25, 2008.
[6] Introduction to HIV types, groups and subtypes. March
3, 2008. Retrieved May 25, 2008.
[7] Hemelaar J, Gouws E, Ghys PD, Osmanov S.; Gouws;
Ghys; Osmanov (March 2006).
Global and regional distribution of HIV-1 genetic subtypes and
recombinants in 2004.
AIDS 20 (16): W13
23. doi:10.1097/01.aids.0000247564.73009.bc. PMID
17053344.
[8] CRF19_cpx is an Evolutionary t HIV-1 Variant Strongly Associated With Rapid Progression to
AIDS in Cuba. EBioMedicine. 28 January 2015.
doi:10.1016/j.ebiom.2015.01.015. Retrieved 17 Feb
2015.
Isolates of HIV-1 and HIV-2 with resistance to antiretro- [9] HIV types, subtypes, groups & strains
viral drugs arise through genetic mutations, which have
been tracked and analyzed. The Stanford HIV Drug Re- [10] Julie Yamaguchi, Ruthie Coey, Ana Vallari, Charlotte
sistance Database and the International AIDS Society
Ngansop, Dora Mbanya, Nicaise Ndembi, Lazare Kaptu, Lutz G. Grtler, Pierre Bodelle, Gerald Schochetpublish lists of the most important of these; rst year listman, Sushil G. Devare, Catherine A. Brennan (January
ing 80 common mutations, and the latest year 93 common
2006). Identication of HIV Type 1 Group N Infections
mutations, and made available through the Stanford HIV
in a Husband and Wife in Cameroon: Viral Genome SeRT and Protease Sequence Database.
[13] Plantier JC, Leoz M, Dickerson JE, De Oliveira F, Cordonnier F, Leme V, Damond F, Robertson DL, Simon F
(August 2009). A new human immunodeciency virus
derived from gorillas. Nature Medicine 15 (8): 8712.
doi:10.1038/nm.2016. PMID 19648927.
[14] New HIV strain discovered. Associated Press (CBC
News). 2009-08-03. Retrieved 2009-08-03.
[15] Donald G. McNeil, Jr. (September 16, 2010). Precursor
to H.I.V. Was in Monkeys for Millennia. New York
Times. Retrieved 2010-09-17. But P appears to have
crossed over from a gorilla; it was discovered only last
year, and in only one woman, who was from Cameroon,
where lowland gorillas are hunted for meat.
[16] HIV-2
[17] CBER - Donor Screening Assays for Infectious Agents
and HIV Diagnostic Assays
[18] Santiago, Mario L.; Range, Friederike; Keele, Brandon
F.; Li, Yingying; Bailes, Elizabeth; Bibollet-Ruche, Frederic; Fruteau, Cecile; No, Ronald; Peeters, Martine;
Brookeld, John F. Y.; Shaw, George M.; Sharp, Paul M.;
Hahn, Beatrice H. (2005). Simian Immunodeciency
Virus Infection in Free-Ranging Sooty Mangabeys (Cercocebus atys atys) from the Ta Forest, Cte d'Ivoire: Implications for the Origin of Epidemic Human Immunodeciency Virus Type 2. Journal of Virology 79 (19):
1251527. doi:10.1128/JVI.79.19.12515-12527.2005.
PMC 1211554. PMID 16160179.
[19] Marx PA, Alcabes PG, Drucker E (2001). Serial human
passage of simian immunodeciency virus by unsterile injections and the emergence of epidemic human immunodeciency virus in Africa. Philos Trans R Soc Lond B Biol
Sci 356 (1410): 91120. doi:10.1098/rstb.2001.0867.
PMC 1088484. PMID 11405938.
[20] http://aidsinfo.nih.gov/guidelines
[21] Human Immunodeciency Virus Type 2 (HIV-2) by New
York State Department of Health AIDS Institute: http:
//www.hivguidelines.org
[22] R Kannangai, S David, G Sridharan. Human immunodeciency virus type 2-A milder, kinder virus: An update.
Indian Journal of Medical Micobiology, (2012) 30(1): 615.
[23] HIV evolving 'into milder form'
55
Chapter 8
HIV/AIDS
This article is about the disease. For the virus, see HIV. large area and is actively spreading.[14] Genetic research
For other uses, see AIDS (disambiguation).
indicates that HIV originated in west-central Africa during the late 19th or early 20th century.[15] AIDS was
rst recognized by the United States Centers for Disease
Human immunodeciency virus infection and acquired immune deciency syndrome (HIV/AIDS) is Control and Prevention (CDC) in 1981 and its cause
HIV infectionwas identied in the early part of the
a spectrum of conditions caused by infection with the
[16]
human immunodeciency virus (HIV).[2][3][4] It may also decade.
be referred to as HIV disease or HIV infection.[5][6] Following initial infection, a person may experience a brief
period of inuenza-like illness. This is typically followed
by a prolonged period without symptoms. As the infection progresses, it interferes more and more with the
immune system, making the person much more susceptible to common infections, like tuberculosis, as well as
opportunistic infections and tumors that do not usually
aect people who have working immune systems. The
late symptoms of the infection are referred to as AIDS.
This stage is often complicated by an infection of the lung
known as pneumocystis pneumonia, severe weight loss,
skin lesions caused by Kaposis sarcoma, or other AIDSdening conditions.
HIV is transmitted primarily via unprotected sexual intercourse (including anal and oral sex), contaminated
blood transfusions, hypodermic needles, and from mother
to child during pregnancy, delivery, or breastfeeding.[7]
Some bodily uids, such as saliva and tears, do not
transmit HIV.[8] Common methods of HIV/AIDS prevention include encouraging and practicing safe sex,
needle-exchange programs, and treating those who are
infected.[9] There is no cure or vaccine; however,
antiretroviral treatment can slow the course of the disease
and may lead to a near-normal life expectancy. While antiretroviral treatment reduces the risk of death and complications from the disease, these medications are expensive and have side eects. Treatment is recommended
as soon as the diagnosis is made.[10] Without treatment,
the average survival time after infection with HIV is
estimated to be 9 to 11 years, depending on the HIV
subtype.[11]
Since its discovery, AIDS has caused an estimated 36
million deaths worldwide (as of 2012).[12] In 2014 it resulted in about 1.2 million deaths and about 36.9 million
people were living with HIV.[13] HIV/AIDS is considered
a pandemica disease outbreak which is present over a
56
57
Main symptoms of
8.1.3 Acquired
drome
Esophagus:
- Sores
Central:
- Malaise
syn-
Main symptoms of
AIDS
- Headache
- Neuropathy
Lymph nodes:
- Lymphadenopathy
Central
- Encephalitis
- Meningitis
Skin:
- Rash
Eyes
- Retinitis
Muscles:
- Myalgia
Gastric:
-Nausea
-Vomiting
Liver and
spleen:
- Enlargement
immunodeciency
[21]
or two weeks.
Lungs
- Pneumocystis
pneumonia
- Tuberculosis
(multiple organs)
- Tumors
Skin
- Tumors
Gastrointestinal
Due to their nonspecic character, these symptoms are
- Esophagitis
not often recognized as signs of HIV infection. Even
- Chronic diarrhea
cases that do get seen by a family doctor or a hospi- Tumors
tal are often misdiagnosed as one of the many common
infectious diseases with overlapping symptoms. Thus, it
Main symptoms of AIDS.
is recommended that HIV be considered in people presenting an unexplained fever who may have risk factors
Acquired immunodeciency syndrome (AIDS) is dened
for the infection.[21]
in terms of either a CD4+ T cell count below 200 cells
per L or the occurrence of specic diseases in association with an HIV infection.[21] In the absence of specic treatment, around half of people infected with HIV
8.1.2 Clinical latency
develop AIDS within ten years.[21] The most common
The initial symptoms are followed by a stage called clini- initial conditions that alert to the presence of AIDS are
cal latency, asymptomatic HIV, or chronic HIV.[5] With- pneumocystis pneumonia (40%), cachexia in the form of
wasting syndrome (20%), and esophageal candidiaout treatment, this second stage of the natural history of HIV
sis.[21] Other common signs include recurring respiratory
[23]
HIV infection can last from about three years to over
[21]
20 years[24] (on average, about eight years).[25] While typ- tract infections.
58
CHAPTER 8. HIV/AIDS
8.2.1
Sexual
Commercial sex workers (including those in pornography) have an increased rate of HIV.[53][54] Rough sex
can be a factor associated with an increased risk of
transmission.[55] Sexual assault is also believed to carry
an increased risk of HIV transmission as condoms are
rarely worn, physical trauma to the vagina or rectum is
likely, and there may be a greater risk of concurrent sexually transmitted infections.[56]
8.3. VIROLOGY
blood or blood product, or medical injections with unsterilised equipment. The risk from sharing a needle during
drug injection is between 0.63 and 2.4% per act, with
an average of 0.8%.[57] The risk of acquiring HIV from
a needle stick from an HIV-infected person is estimated
as 0.3% (about 1 in 333) per act and the risk following
mucous membrane exposure to infected blood as 0.09%
(about 1 in 1000) per act.[42] In the United States intravenous drug users made up 12% of all new cases of HIV
in 2009,[44] and in some areas more than 80% of people
who inject drugs are HIV positive.[7]
59
fant decrease the risk of transmission in those who do
breastfeed.[68] Many of these measures are however not
available in the developing world.[67] If blood contaminates food during pre-chewing it may pose a risk of
transmission.[63]
8.3 Virology
Main article: HIV
HIV is the cause of the spectrum of disease known
HIV is transmitted in about 93% of blood transfusions using infected blood.[57] In developed countries the risk of
acquiring HIV from a blood transfusion is extremely low
(less than one in half a million) where improved donor selection and HIV screening is performed;[7] for example,
in the UK the risk is reported at one in ve million[58] and
in the United States it was one in 1.5 million in 2008.[59]
In low income countries, only half of transfusions may
be appropriately screened (as of 2008),[60] and it is estimated that up to 15% of HIV infections in these areas come from transfusion of infected blood and blood
products, representing between 5% and 10% of global
infections.[7][61]
Unsafe medical injections play a signicant role in HIV
spread in sub-Saharan Africa. In 2007, between 12 and
17% of infections in this region were attributed to med- Diagram of a HIV virion structure
ical syringe use.[62] The World Health Organization estimates the risk of transmission as a result of a medical injection in Africa at 1.2%.[62] Signicant risks are also associated with invasive procedures, assisted delivery, and
dental care in this area of the world.[62]
People giving or receiving tattoos, piercings, and
scarication are theoretically at risk of infection but no
conrmed cases have been documented.[63] It is not possible for mosquitoes or other insects to transmit HIV.[64]
8.2.3
Mother-to-child
HIV can be transmitted from mother to child during pregnancy, during delivery, or through breast milk.[65][66] This
is the third most common way in which HIV is transmitted globally.[7] In the absence of treatment, the risk
of transmission before or during birth is around 20%
and in those who also breastfeed 35%.[65] As of 2008,
vertical transmission accounted for about 90% of cases
of HIV in children.[65] With appropriate treatment the
risk of mother-to-child infection can be reduced to about
1%.[65] Preventive treatment involves the mother taking
antiretrovirals during pregnancy and delivery, an elective caesarean section, avoiding breastfeeding, and administering antiretroviral drugs to the newborn.[67] Antiretrovirals when taken by either the mother or the in-
60
double-stranded DNA by a virally encoded reverse transcriptase that is transported along with the viral genome
in the virus particle. The resulting viral DNA is then imported into the cell nucleus and integrated into the cellular DNA by a virally encoded integrase and host cofactors.[73] Once integrated, the virus may become latent,
allowing the virus and its host cell to avoid detection by
the immune system.[74] Alternatively, the virus may be
transcribed, producing new RNA genomes and viral proteins that are packaged and released from the cell as new
virus particles that begin the replication cycle anew.[75]
HIV is now known to spread between CD4+ T cells
by two parallel routes: cell-free spread and cell-to-cell
spread, i.e. it employs hybrid spreading mechanisms.[76]
In the cell-free spread, virus particles bud from an infected T cell, enter the blood/extracellular uid and then
infect another T cell following a chance encounter.[76]
HIV can also disseminate by direct transmission from one
cell to another by a process of cell-to-cell spread.[77][78]
The hybrid spreading mechanisms of HIV contribute
to the viruss ongoing replication against antiretroviral
therapies.[76][79]
Two types of HIV have been characterized: HIV-1 and
HIV-2. HIV-1 is the virus that was originally discovered
(and initially referred to also as LAV or HTLV-III). It is
more virulent, more infective,[80] and is the cause of the
majority of HIV infections globally. The lower infectivity of HIV-2 as compared with HIV-1 implies that fewer
people exposed to HIV-2 will be infected per exposure.
Because of its relatively poor capacity for transmission,
HIV-2 is largely conned to West Africa.[81]
8.4 Pathophysiology
CHAPTER 8. HIV/AIDS
ated with activation of CD8+ T cells, which kill HIVinfected cells, and subsequently with antibody production, or seroconversion. The CD8+ T cell response is
thought to be important in controlling virus levels, which
peak and then decline, as the CD4+ T cell counts recover.
A good CD8+ T cell response has been linked to slower
disease progression and a better prognosis, though it does
not eliminate the virus.[83]
Ultimately, HIV causes AIDS by depleting CD4+ T
cells. This weakens the immune system and allows
opportunistic infections. T cells are essential to the immune response and without them, the body cannot ght
infections or kill cancerous cells. The mechanism of
CD4+ T cell depletion diers in the acute and chronic
phases.[84] During the acute phase, HIV-induced cell lysis
and killing of infected cells by cytotoxic T cells accounts
for CD4+ T cell depletion, although apoptosis may also be
a factor. During the chronic phase, the consequences of
generalized immune activation coupled with the gradual
loss of the ability of the immune system to generate new
T cells appear to account for the slow decline in CD4+ T
cell numbers.[85]
Although the symptoms of immune deciency characteristic of AIDS do not appear for years after a person is infected, the bulk of CD4+ T cell loss occurs during the rst
weeks of infection, especially in the intestinal mucosa,
which harbors the majority of the lymphocytes found in
the body.[86] The reason for the preferential loss of mucosal CD4+ T cells is that the majority of mucosal CD4+
T cells express the CCR5 protein which HIV uses as a coreceptor to gain access to the cells, whereas only a small
fraction of CD4+ T cells in the bloodstream do so.[87] A
specic genetic change that alters the CCR5 protein when
present in both chromosomes very eectively prevents
HIV-1 infection.[88]
8.5. DIAGNOSIS
61
the WHO disease staging system for HIV infection and
disease,[19] and the CDC classication system for HIV
infection.[95] The CDC's classication system is more
frequently adopted in developed countries. Since the
WHO's staging system does not require laboratory tests,
it is suited to the resource-restricted conditions encountered in developing countries, where it can also be used
to help guide clinical management. Despite their dierences, the two systems allow comparison for statistical
purposes.[18][19][95]
staged based on the presence of certain signs or symptoms.[19] HIV screening is recommended by the United
States Preventive Services Task Force for all people 15
years to 65 years of age including all pregnant women.[92]
Additionally, testing is recommended for those at high
risk, which includes anyone diagnosed with a sexually
transmitted illness.[22] In many areas of the world, a third
of HIV carriers only discover they are infected at an advanced stage of the disease, when AIDS or severe immunodeciency has become apparent.[22]
8.5.1
HIV testing
8.5.2
Classications
The World Health Organization rst proposed a denition for AIDS in 1986.[19] Since then, the WHO classication has been updated and expanded several times, with
the most recent version being published in 2007.[19] The
WHO system uses the following categories:
Primary HIV infection: May be either asymptomatic or associated with acute retroviral
syndrome.[19]
Stage I: HIV infection is asymptomatic with a
CD4+ T cell count (also known as CD4 count)
greater than 500 per microlitre (l or cubic mm)
of blood.[19] May include generalized lymph node
enlargement.[19]
Stage II: Mild symptoms which may include minor
mucocutaneous manifestations and recurrent upper
respiratory tract infections. A CD4 count of less
than 500/l.[19]
Stage III: Advanced symptoms which may include
unexplained chronic diarrhea for longer than a
month, severe bacterial infections including tuberculosis of the lung, and a CD4 count of less than
350/l.[19]
Stage IV or AIDS: severe symptoms which include toxoplasmosis of the brain, candidiasis of the
esophagus, trachea, bronchi or lungs and Kaposis
sarcoma. A CD4 count of less than 200/l.[19]
The United States Center for Disease Control and Prevention also created a classication system for HIV, and
updated it in 2008 and 2014.[95][96] This system classies
HIV infections based on CD4 count and clinical symptoms, and describes the infection in ve groups.[96] In
those greater than six years of age it is:[96]
Stage 0: the time between a negative or indeterminate HIV test followed less than 180 days by a positive test
Stage 1: CD4 count 500 cells/l and no AIDS
dening conditions
Stage 2: CD4 count 200 to 500 cells/l and no AIDS
dening conditions
62
CHAPTER 8. HIV/AIDS
Stage 3: CD4 count 200 cells/l or AIDS dening Circumcision in Sub-Saharan Africa reduces the acconditions
quisition of HIV by heterosexual men by between 38%
and 66% over 24 months.[102] Based on these stud Unknown: if insucient information is available to ies, the World Health Organization and UNAIDS both
make any of the above classications
recommended male circumcision as a method of preventing female-to-male HIV transmission in 2007.[103]
For surveillance purposes, the AIDS diagnosis still stands Whether it protects against male-to-female transmiseven if, after treatment, the CD4+ T cell count rises to sion is disputed[104][105] and whether it is of benet in
above 200 per L of blood or other AIDS-dening ill- developed countries and among men who have sex with
nesses are cured.[18]
men is undetermined.[106][107][108] The International Antiviral Society, however, does recommend for all sexually
active heterosexual males and that it be discussed as an
option with men who have sex with men.[109] Some ex8.6 Prevention
perts fear that a lower perception of vulnerability among
circumcised men may cause more sexual risk-taking beMain article: Prevention of HIV/AIDS
havior, thus negating its preventive eects.[110]
Programs encouraging sexual abstinence do not appear to
aect subsequent HIV risk.[111] Evidence of any benet
from peer education is equally poor.[112] Comprehensive
sexual education provided at school may decrease high
risk behavior.[113] A substantial minority of young people
continues to engage in high-risk practices despite knowing about HIV/AIDS, underestimating their own risk of
becoming infected with HIV.[114] Voluntary counseling
and testing people for HIV does not aect risky behavior in those who test negative but does increase condom
use in those who test positive.[115] It is not known whether
treating other sexually transmitted infections is eective
in preventing HIV.[51]
8.6.2 Pre-exposure
Antiretroviral treatment among people with HIV whose
CD4 count 550 cells/L is a very eective way to prevent HIV infection of their partner (a strategy known
as treatment as prevention, or TASP).[116] TASP is associated with a 10 to 20 fold reduction in transmission risk.[117][116] Pre-exposure prophylaxis (PrEP) with
a daily dose of the medications tenofovir, with or withAIDS Clinic, McLeod Ganj, Himachal Pradesh, India, 2010
out emtricitabine, is eective in a number of groups including men who have sex with men, couples where one
is HIV positive, and young heterosexuals in Africa.[100]
It may also be eective in intravenous drug users with
8.6.1 Sexual contact
a study nding a decrease in risk of 0.7 to 0.4 per 100
[118]
Consistent condom use reduces the risk of HIV trans- person years.
mission by approximately 80% over the long term.[97] Universal precautions within the health care environment
When condoms are used consistently by a couple in which are believed to be eective in decreasing the risk of
one person is infected, the rate of HIV infection is less HIV.[119] Intravenous drug use is an important risk factor
than 1% per year.[98] There is some evidence to sug- and harm reduction strategies such as needle-exchange
gest that female condoms may provide an equivalent level programmes and opioid substitution therapy appear efof protection.[99] Application of a vaginal gel containing fective in decreasing this risk.[120][121]
tenofovir (a reverse transcriptase inhibitor) immediately
before sex seems to reduce infection rates by approximately 40% among African women.[100] By contrast, use 8.6.3 Post-exposure
of the spermicide nonoxynol-9 may increase the risk of
transmission due to its tendency to cause vaginal and rec- A course of antiretrovirals administered within 48 to
72 hours after exposure to HIV-positive blood or genital irritation.[101]
8.7. TREATMENT
tal secretions is referred to as post-exposure prophylaxis
(PEP).[122] The use of the single agent zidovudine reduces the risk of a HIV infection ve-fold following a
needle-stick injury.[122] As of 2013, the prevention regimen recommended in the United States consists of three
medicationstenofovir, emtricitabine and raltegravir
as this may reduce the risk further.[123]
PEP treatment is recommended after a sexual assault
when the perpetrator is known to be HIV positive, but
is controversial when their HIV status is unknown.[124]
The duration of treatment is usually four weeks[125] and
is frequently associated with adverse eectswhere zidovudine is used, about 70% of cases result in adverse
eects such as nausea (24%), fatigue (22%), emotional
distress (13%) and headaches (9%).[42]
8.6.4
63
(HAART) which slows progression of the disease.[134] As
of 2010 more than 6.6 million people were taking them
in low and middle income countries.[135] Treatment also
includes preventive and active treatment of opportunistic
infections.
Mother-to-child
8.6.5
Vaccination
8.7 Treatment
Main article: Management of HIV/AIDS
Current HAART options are combinations (or cocktails) consisting of at least three medications belonging
to at least two types, or classes, of antiretroviral
agents.[136] Initially treatment is typically a nonnucleoside reverse transcriptase inhibitor (NNRTI) plus
two nucleoside analogue reverse transcriptase inhibitors
(NRTIs).[137] Typical NRTIs include: zidovudine
(AZT) or tenofovir (TDF) and lamivudine (3TC) or
emtricitabine (FTC).[137] Combinations of agents which
include protease inhibitors (PI) are used if the above
regimen loses eectiveness.[136]
The World Health Organization and United States recommends antiretrovirals in people of all ages including
pregnant women as soon as the diagnosis is made regardless of CD4 count.[10][109][138] Once treatment is begun
it is recommended that it is continued without breaks
or holidays.[22] Many people are diagnosed only after
treatment ideally should have begun.[22] The desired outcome of treatment is a long term plasma HIV-RNA count
below 50 copies/mL.[22] Levels to determine if treatment
is eective are initially recommended after four weeks
and once levels fall below 50 copies/mL checks every
three to six months are typically adequate.[22] Inadequate
control is deemed to be greater than 400 copies/mL.[22]
Based on these criteria treatment is eective in more than
95% of people during the rst year.[22]
There is currently no cure or eective HIV vaccine. Benets of treatment include a decreased risk of proTreatment consists of highly active antiretroviral therapy gression to AIDS and a decreased risk of death.[139] In
64
CHAPTER 8. HIV/AIDS
8.7.2
Opportunistic infections
Measures to prevent opportunistic infections are eective in many people with HIV/AIDS. In addition to improving current disease, treatment with antiretrovirals
reduces the risk of developing additional opportunistic
infections.[146] Adults and adolescents who are living with
HIV (even on anti-retroviral therapy) with no evidence
of active tuberculosis in settings with high tuberculosis burden should receive isoniazid preventive therapy
(IPT), the tuberculin skin test can be used to help decide if IPT is needed.[151] Vaccination against hepatitis
A and B is advised for all people at risk of HIV before they become infected; however it may also be given
after infection.[152] Trimethoprim/sulfamethoxazole prophylaxis between four and six weeks of age and ceasing breastfeeding in infants born to HIV positive mothers is recommended in resource limited settings.[153] It is
also recommended to prevent PCP when a persons CD4
count is below 200 cells/uL and in those who have or
have previously had PCP.[154] People with substantial immunosuppression are also advised to receive prophylac-
tic therapy for toxoplasmosis and Cryptococcus meningitis.[155] Appropriate preventive measures have reduced
the rate of these infections by 50% between 1992 and
1997.[156]
8.7.3 Diet
Main article: Nutrition and HIV/AIDS
The World Health Organization (WHO) has issued
recommendations regarding nutrient requirements in
HIV/AIDS.[157] A generally healthy diet is promoted.
Some evidence has shown a benet from micronutrient
supplements.[158] Evidence for supplementation with
selenium is mixed with some tentative evidence of
benet.[159] There is some evidence that vitamin A
supplementation in children reduces mortality and improves growth.[158] In Africa in nutritionally compromised pregnant and lactating women a multivitamin supplementation has improved outcomes for both mothers and children.[158] Dietary intake of micronutrients
at RDA levels by HIV-infected adults is recommended
by the WHO; higher intake of vitamin A, zinc, and
iron can produce adverse eects in HIV positive adults,
and is not recommended unless there is documented
deciency.[157][160][161][162]
8.8 Prognosis
8.9. EPIDEMIOLOGY
65
sis varies between people, and both the CD4 count and
viral load are useful for predicted outcomes.[21] Without treatment, average survival time after infection with
HIV is estimated to be 9 to 11 years, depending on
the HIV subtype.[11] After the diagnosis of AIDS, if
treatment is not available, survival ranges between 6
and 19 months.[168][169] HAART and appropriate prevention of opportunistic infections reduces the death rate
by 80%, and raises the life expectancy for a newly diagnosed young adult to 2050 years.[167][170][171] This
% of HIV among young adults (1549)
is between two thirds[170] and nearly that of the gen- Estimated prevalence in[187]
[22][172]
per
country
as
of
2011.
eral population.
If treatment is started late in the
infection, prognosis is not as good:[22] for example, if
treatment is begun following the diagnosis of AIDS,
life expectancy is ~1040 years.[22][167] Half of infants
born with HIV die before two years of age without
treatment.[153]
The primary causes of death from HIV/AIDS are
opportunistic infections and cancer, both of which are
frequently the result of the progressive failure of the immune system.[156][173] Risk of cancer appears to increase
once the CD4 count is below 500/L.[22] The rate of
clinical disease progression varies widely between individuals and has been shown to be aected by a number
of factors such as a persons susceptibility and immune
function;[174] their access to health care, the presence of
co-infections;[168][175] and the particular strain (or strains)
of the virus involved.[176][177]
8.9 Epidemiology
Main article: Epidemiology of HIV/AIDS
HIV/AIDS is a global pandemic.[188] As of 2012, approximately 35.3 million people have HIV worldwide
with the number of new infections that year being about
2.3 million.[189] This is down from 3.1 million new infections in 2001.[189] Of these approximately 16.8 million
are women and 3.4 million are less than 15 years old.[135]
It resulted in about 1.34 million deaths in 2013,[190] down
66
CHAPTER 8. HIV/AIDS
8.10 History
Main article: History of HIV/AIDS
8.10.1
Discovery
At one point, the CDC coined the phrase the 4H disease, since the syndrome seemed to aect homosexuals, heroin users, hemophiliacs, and Haitians.[207][208] In
the general press, the term GRID, which stood for gayrelated immune deciency, had been coined.[209] However, after determining that AIDS was not isolated to the
gay community,[206] it was realized that the term GRID
was misleading and the term AIDS was introduced at a
meeting in July 1982.[210] By September 1982 the CDC
started referring to the disease as AIDS.[211]
In 1983, two separate research groups led by Robert
Gallo and Luc Montagnier declared that a novel retrovirus may have been infecting people with AIDS, and
published their ndings in the same issue of the journal
Science.[212][213] Gallo claimed that a virus his group had
isolated from a person with AIDS was strikingly similar in
shape to other human T-lymphotropic viruses (HTLVs)
his group had been the rst to isolate. Gallos group
called their newly isolated virus HTLV-III. At the same
time, Montagniers group isolated a virus from a person
presenting with swelling of the lymph nodes of the neck
and physical weakness, two characteristic symptoms of
AIDS. Contradicting the report from Gallos group, Montagnier and his colleagues showed that core proteins of
this virus were immunologically dierent from those of
HTLV-I. Montagniers group named their isolated virus
lymphadenopathy-associated virus (LAV).[203] As these
two viruses turned out to be the same, in 1986, LAV and
HTLV-III were renamed HIV.[214]
8.10.2 Origins
Left to right: the African green monkey source of SIV, the sooty
mangabey source of HIV-2 and the chimpanzee source of HIV-1
67
bly because of a genomic fusion of two viral resistance of New York and San Francisco was estimated at 5%,
genes.[217] HIV-1 is thought to have jumped the species suggesting that several thousand individuals in the counbarrier on at least three separate occasions, giving rise to try had been infected.[227]
the three groups of the virus, M, N, and O.[218]
There is evidence that humans who participate in
bushmeat activities, either as hunters or as bushmeat ven- 8.11
dors, commonly acquire SIV.[219] However, SIV is a weak
virus which is typically suppressed by the human immune 8.11.1
system within weeks of infection. It is thought that several transmissions of the virus from individual to individual in quick succession are necessary to allow it enough
time to mutate into HIV.[220] Furthermore, due to its relatively low person-to-person transmission rate, SIV can
only spread throughout the population in the presence of
one or more high-risk transmission channels, which are
thought to have been absent in Africa before the 20th century.
Specic proposed high-risk transmission channels, allowing the virus to adapt to humans and spread throughout
the society, depend on the proposed timing of the animalto-human crossing. Genetic studies of the virus suggest that the most recent common ancestor of the HIV1 M group dates back to circa 1910.[221] Proponents of
this dating link the HIV epidemic with the emergence of
colonialism and growth of large colonial African cities,
leading to social changes, including a higher degree of
sexual promiscuity, the spread of prostitution, and the
accompanying high frequency of genital ulcer diseases
(such as syphilis) in nascent colonial cities.[222] While
transmission rates of HIV during vaginal intercourse are
low under regular circumstances, they are increased many
fold if one of the partners suers from a sexually transmitted infection causing genital ulcers. Early 1900s colonial cities were notable due to their high prevalence of
prostitution and genital ulcers, to the degree that, as of
1928, as many as 45% of female residents of eastern
Kinshasa were thought to have been prostitutes, and, as
of 1933, around 15% of all residents of the same city had
syphilis.[222]
An alternative view holds that unsafe medical practices
in Africa after World War II, such as unsterile reuse
of single use syringes during mass vaccination, antibiotic and anti-malaria treatment campaigns, were the initial vector that allowed the virus to adapt to humans and
spread.[220][223][224]
Ryan White became a poster child for HIV after being expelled
from school because he was infected.[228]
Main article:
HIV/AIDS
68
CHAPTER 8. HIV/AIDS
with any deadly and transmissible illness.[231]
Symbolic AIDS stigmathe use of HIV/AIDS to express attitudes toward the social groups or lifestyles
perceived to be associated with the disease.[231]
Courtesy AIDS stigmastigmatization of people
connected to the issue of HIV/AIDS or HIVpositive people.[232]
8.12. RESEARCH
8.11.4
Media portrayal
69
8.11.6 Misconceptions
Main articles: Misconceptions about HIV/AIDS, AIDS
denialism and Discredited HIV/AIDS origins theories
There are many misconceptions about HIV and AIDS.
Three of the most common are that AIDS can spread
through casual contact, that sexual intercourse with a
virgin will cure AIDS,[255][256][257] and that HIV can
infect only gay men and drug users. In 2014, some
among the British public wrongly thought you could get
HIV from kissing (16%), sharing a glass (5%), spitting
(16%), a public toilet seat (4%), and coughing or sneezing (5%).[258] Other misconceptions are that any act of
anal intercourse between two uninfected gay men can
lead to HIV infection, and that open discussion of HIV
and homosexuality in schools will lead to increased rates
of AIDS.[259][260]
A small group of individuals continue to dispute the
connection between HIV and AIDS,[261] the existence
of HIV itself, or the validity of HIV testing and treatment methods.[262][263] These claims, known as AIDS denialism, have been examined and rejected by the scientic community.[264] However, they have had a signicant political impact, particularly in South Africa, where
the governments ocial embrace of AIDS denialism
(19992005) was responsible for its ineective response
to that countrys AIDS epidemic, and has been blamed
for hundreds of thousands of avoidable deaths and HIV
infections.[265][266][267]
Several discredited conspiracy theories have held that
HIV was created by scientists, either inadvertently or deliberately. Operation INFEKTION was a worldwide Soviet active measures operation to spread the claim that the
United States had created HIV/AIDS. Surveys show that
a signicant number of people believed and continue
to believe in such claims.[268]
8.12 Research
Main article: HIV/AIDS research
8.11.5
Criminal transmission
70
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News. Retrieved April 9, 2013.
government of murder. Lancet 361 (9363): 1105.
doi:10.1016/S0140-6736(03)12909-1. PMID 12672319.
[252] HIV killer ruled dangerous oender. CBC News. Retrieved April 9, 2013.
[267] Cohen J (2000). South Africas new enemy. Science 288
[253] A fraudster, not a murderer. National Post. Retrieved
(5474): 216870. doi:10.1126/science.288.5474.2168.
April 9, 2013.
PMID 10896606.
[254] HIV-Specic Criminal Laws. cdc.gov. June 30, 2014. [268] Boghardt, Thomas (2009). Operation INFEKTION SoRetrieved November 22, 2014.
viet Bloc Intelligence and Its AIDS Disinformation Campaign. Central Intelligence Agency.
[255] "Virgin cure: Three women killed to cure Aids.
International Herald Tribune. February 28, 2013. Retrieved September 14, 2013.
[256] Jenny, Carole (2010). Child Abuse and Neglect: Diagnosis, Treatment and Evidence Expert Consult. Elsevier
Health Sciences. p. 187. ISBN 978-1-4377-3621-2.
[257] Klot, Jennifer; Monica Kathina Juma (2011). HIV/AIDS,
Gender, Human Security and Violence in Southern Africa.
Pretoria: Africa Institute of South Africa. p. 47. ISBN
0-7983-0253-4.
81
Chapter 9
Pathophysiology of HIV/AIDS
The HIV virus is commonly transmitted via unprotected
sexual activity, blood transfusions, hypodermic needles,
and from mother to child. Upon acquisition of the virus,
the virus replicates inside and kills T helper cells, which
are required for almost all adaptive immune responses.
There is an initial period of inuenza-like illness, and then
a latent, asymptomatic phase. When the CD4 lymphocyte count falls below 200 cells/ml of blood, the HIV host
has progressed to AIDS, a condition characterized by deciency in cell-mediated immunity and the resulting increased susceptibility to opportunistic infections and certain forms of cancer.
9.1 Immunology
After the virus enters the body there is a period of rapid
viral replication, leading to an abundance of virus in the
peripheral blood. During primary infection, the level
of HIV may reach several million virus particles per
milliliter of blood.[1]
This response is accompanied by a marked drop in the
numbers of circulating CD4+ T cells. This acute viremia
is associated in virtually all people with the activation of
CD8+ T cells, which kill HIV-infected cells, and subsequently with antibody production, or seroconversion.
The CD8+ T cell response is thought to be important in
controlling virus levels, which peak and then decline, as
the CD4+ T cell counts rebound. A good CD8+ T cell
response has been linked to slower disease progression
and a better prognosis, though it does not eliminate the
virus.[2]
During the acute phase, HIV-induced cell lysis and killing
of infected cells by cytotoxic T cells accounts for CD4+
T cell depletion, although apoptosis may also be a factor.
During the chronic phase, the consequences of generalized immune activation coupled with the gradual loss of
the ability of the immune system to generate new T cells
appear to account for the slow decline in CD4+ T cell
numbers.
However, the symptoms of immune deciency characteristic of AIDS do not appear for years after a person is infected, the bulk of CD4+ T cell loss occurs during the rst
82
9.5. REFERENCES
83
9.5 References
[1] Piatak, M., Jr, Saag, M. S., Yang, L. C., Clark,
S. J., Kappes, J. C., Luk, K. C., Hahn, B. H.,
Shaw, G. M. and Lifson, J.D. (1993). High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science 259
Bibcode:1993Sci...259.1749P.
(5102): 17491754.
doi:10.1126/science.8096089. PMID 8096089.
[2] Pantaleo G, Demarest JF, Schacker T, Vaccarezza M,
Cohen OJ, Daucher M, Graziosi C, Schnittman SS,
Quinn TC, Shaw GM, Perrin L, Tambussi G, Lazzarin A, Sekaly RP, Soudeyns H, Corey L, Fauci
AS. (1997). The qualitative nature of the primary
immune response to HIV infection is a prognosticator of disease progression independent of the initial
level of plasma viremia. Proc Natl Acad Sci U S
A. 94 (1): 254258. Bibcode:1997PNAS...94..254P.
doi:10.1073/pnas.94.1.254.
PMC 19306.
PMID
8990195.
[3] Mehandru S, Poles MA, Tenner-Racz K, Horowitz A,
Hurley A, Hogan C, Boden D, Racz P, Markowitz M
(September 2004). Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from eector sites in the gastrointestinal tract. J.
Exp. Med. 200 (6): 76170. doi:10.1084/jem.20041196.
PMC 2211967. PMID 15365095.
[4] Brenchley JM, Schacker TW, Ru LE, Price DA, Taylor
JH, Beilman GJ, Nguyen PL, Khoruts A, Larson M, Haase
AT, Douek DC (September 2004). CD4+ T cell depletion during all stages of HIV disease occurs predominantly
in the gastrointestinal tract. J. Exp. Med. 200 (6): 749
59. doi:10.1084/jem.20040874. PMC 2211962. PMID
15365096.
[5] Appay V, Sauce D (January 2008). Immune activation and inammation in HIV-1 infection: causes
and consequences. J. Pathol. 214 (2): 23141.
doi:10.1002/path.2276. PMID 18161758.
[6] Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, Kazzaz Z, Bornstein E, Lambotte O, Altmann D, Blazar BR, Rodriguez B, Teixeira-Johnson L,
Landay A, Martin JN, Hecht FM, Picker LJ, Lederman
MM, Deeks SG, Douek DC (December 2006). Microbial translocation is a cause of systemic immune activation
in chronic HIV infection. Nat. Med. 12 (12): 136571.
doi:10.1038/nm1511. PMID 17115046.
[7] Textbook of Pathology by Harsh Mohan, ISBN 81-8061368-2
Chapter 10
Diagnosis of HIV/AIDS
sensitivity: The percentage of the results that will be
positive when HIV is present
specicity: The percentage of the results that will be
negative when HIV is not present.
All diagnostic tests have limitations, and sometimes their
use may produce erroneous or questionable results.
False positive: The test incorrectly indicates that
HIV is present in a non-infected person.
False negative: The test incorrectly indicates that
HIV is absent in an infected person.
Nonspecic reactions, hypergammaglobulinemia, or the
presence of antibodies directed to other infectious agents
that may be antigenically similar to HIV can produce false
positive results. Autoimmune diseases, such as systemic
lupus erythematosus, have also rarely caused false posHIV tests are used to detect the presence of the human itive results. Most false negative results are due to the
immunodeciency virus (HIV), the virus that causes window period.
acquired immunodeciency syndrome (AIDS), in serum,
saliva, or urine. Such tests may detect antibodies,
antigens, or RNA.
10.3 Principles
Randall L. Tobias, former U.S. Global AIDS Coordinator, being
publicly tested for HIV in Ethiopia in an eort to reduce the stigma
of being tested.[1]
Tests selected to screen donor blood and tissue must provide a high degree of condence that HIV will be detected
if present (that is, a high sensitivity is required). A combination of antibody, antigen and nucleic acid tests are
used by blood banks in Western countries. The World
Health Organization estimated that, as of 2000, inadequate blood screening had resulted in 1 million new HIV
infections worldwide.
10.2 Terminology
The window period is the time from infection until a test
can detect any change. The average window period with
HIV-1 antibody tests is 25 days for subtype B. Antigen
testing cuts the window period to approximately 16 days
and NAT (Nucleic Acid Testing) further reduces this period to 12 days.[2]
10.3.2
10.3.4
Condentiality
85
Considerable controversy exists over the ethical obligations of health care providers to inform the sexual partners of individuals infected with HIV that they are at
risk of contracting the virus.[7] Some legal jurisdictions
permit such disclosure, while others do not. More state
funded testing sites are now using condential forms of
testing. This allows for monitoring of infected individuals
easily, compared to anonymous testing that has a number
attached to the positive test results. Controversy exists
over privacy issues.
In developing countries, home-based HIV testing and
counseling (HBHTC) is an emerging approach for addressing condentiality issues. HBHTC allows individuals, couples, and families to learn their HIV status in
the convenience and privacy of their home environment.
Rapid HIV tests are most often used, so results are available for the client between 15 and 30 minutes. Furthermore, when an HIV positive result is communicated, the
HTC provider can oer appropriate linkages for prevention, care, and treatment.[8]
10.3.5
Anonymous testing
86
10.4.2
ELISA
The enzyme-linked immunosorbent assay (ELISA), or enzyme immunoassay (EIA), was the rst screening test
commonly employed for HIV. It has a high sensitivity.
In an ELISA test, a persons serum is diluted 400-fold
and applied to a plate to which HIV antigens have been
attached. If antibodies to HIV are present in the serum,
they may bind to these HIV antigens. The plate is then
washed to remove all other components of the serum. A
specially prepared "secondary antibody" an antibody
that binds to human antibodies is then applied to the
plate, followed by another wash. This secondary antibody
is chemically linked in advance to an enzyme. Thus the
plate will contain enzyme in proportion to the amount of
secondary antibody bound to the plate. A substrate for
the enzyme is applied, and catalysis by the enzyme leads
to a change in color or uorescence. ELISA results are reported as a number; the most controversial aspect of this
test is determining the cut-o point between a positive
and negative result.
10.4.3
ELISA dongle
Researchers from a university have produced ELISA dongle and have tested in Africa which can test HIV, and
syphilis. The dongle can be used in any smartphones
without additional battery, need only 15 minutes to see
the result of a tiny drop of blood. The manufacturing
cost of the dongle is only $34 each.[18]
10.4.4
Western blot
Like the ELISA procedure, the western blot is an antibody detection test. However, unlike the ELISA method,
Western blot test results. The rst two strips are a negative and a
positive control, respectively. The others are actual tests.
87
HIV-2.[20]
The HIV proteins used in western blotting can be produced by recombinant DNA in a technique called recombinant immunoblot assay (RIBA).[21]
10.4.5
Rapid antibody tests are qualitative immunoassays intended for use in point-of-care testing to aid in the diagnosis of HIV infection. These tests should be used in conjunction with the clinical status, history, and risk factors
of the person being tested. The positive predictive value
of Rapid Antibody Tests in low-risk populations has not
been evaluated. These tests should be used in appropriate
multi-test algorithms designed for statistical validation of
rapid HIV test results.
If no antibodies to HIV are detected, this does not mean
the person has not been infected with HIV. It may take
several months after HIV infection for the antibody response to reach detectable levels, during which time rapid
testing for antibodies to HIV will not be indicative of true
infection status. For most people, HIV antibodies reach
a detectable level after two to six weeks.
Although these tests have high specicity, false positives
do occur. Any positive test result should be conrmed by
a lab using the western blot.
88
such as HIV-I GAG, HIV-II GAG, HIV-env, or the HIVpol.[34][35] Since these tests are relatively expensive, the
blood is screened by rst pooling some 8-24 samples and
testing these together; if the pool tests positive, each sample is retested individually. Although this results in a dramatic decrease in cost, the dilution of the virus in the
pooled samples decreases the eective sensitivity of the
test, lengthening the window period by 4 days (assum-
89
10.7 Screening
10.9 Criticisms
10.9.1 Oral tests
90
tives in NYC DOHMH, the CDC still continues to support the use of noninvasive oral uid specimens due to
their popularity in health clinics and convenience of use.
The director of the HIV control program for public health
at Seattle King county, reported OraQuick failed to spot
at least 8 percent of 133 people found to be infected with
a comparable diagnostic test.[41] Strategies implemented
to determine quality control and false positive rates were
implemented. It is to be understood that any reactive
OraQuick test result is a preliminary positive result and
will always require a conrmatory test, regardless of the
mean of testing (venipuncture whole blood, ngerstick
whole blood or oral mucosal transudate uid).[42] Several
other testing sites who did not experience a spike in false
positive rates continue to use OraSures OraQuick HIV
Anti-body Testing.[43][44]
10.9.2
AIDS denialism
HIV tests have been criticized by AIDS denialists (a [8] Getting in the Door: Home-Based HIV Testing and
fringe group whose members believe that HIV either does
Counseling in Kenya. Aidstar-One. Retrieved 2 Novemnot exist or is harmless). The accuracy of serologic testber 2013.
ing has been veried by isolation and culture of HIV and
[9] Armstrong WS, Taege AJ (April 2007). HIV screening
by detection of HIV RNA by PCR, which are widely
for all: the new standard of care. Cleve Clin J Med 74 (4):
[26][27]
While
accepted "gold standards" in microbiology.
297301. doi:10.3949/ccjm.74.4.297. PMID 17438679.
AIDS denialists focus on individual components of HIV
testing, the combination of ELISA and Western blot used [10] CDC fact sheet. Archived from the original on 16
September 2008.
for the diagnosis of HIV is remarkably accurate, with very
low false-positive and -negative rates as described above. [11] Community Health Centers Integrate Rapid HIV ScreenThe views of AIDS denialists are based on highly selecing Into Routine Primary Care, Leading to Signicant
tive analysis of mostly outdated scientic papers; there
Increases in Testing Rates. Agency for Healthcare Reis broad scientic consensus that HIV is the cause of
search and Quality. 5 April 2013. Retrieved 10 May
AIDS.[45][46][47]
2013.
There have been a number of cases of fraudulent tests [13] Skip CDC - HIV Testing Basics for Consumers, from the
being sold via mail order or the Internet to the general
Seattle and King County Public Health Department. Acpublic. In 1997, a California man was indicted on mail
cessed 21 February 2007.
fraud and wire charges for selling supposed home test kits.
[14] C B Hare, B L Pappalardo, M P Busch, B Phelps,
In 2004, the US Federal Trade Commission asked FedS S Alexander, C Ramstead, J A Levy, F M Hecht
eral Express and US Customs to conscate shipments of
(2004). Negative HIV antibody test results among indithe Discreet home HIV test kits, produced by Gregory
viduals treated with antiretroviral therapy (ART) during
Stephen Wong of Vancouver, BC.[48] In February 2005,
acute/early infection. The XV International AIDS Conthe US FDA issued a warning against using the rapid HIV
ference. pp. Abstract no. MoPeB3107.
test kits and other home use kits marketed by Globus Me[15] Ridzon R, Gallagher K, Ciesielski C, et al. (1997).
dia of Montreal, Canada.
10.11 References
[1] Blacklist of English teachers suspected of having AIDS
pursued. This image of Randall L. Tobias is used in a Korean news article suggesting that foreign English teachers
residing in Korea are at risk for AIDS. Accessed 16 Feb.,
2010.
Simultaneous transmission of human immunodeciency virus and hepatitis C virus from a needlestick injury. N Engl J Med 336 (13): 91922.
doi:10.1056/NEJM199703273361304. PMID 9070472.
10.11. REFERENCES
[18] Mariella Moon. Test for HIV in just 15 minutes with this
$34 smartphone dongle. Retrieved February 6, 2015.
[19] Bartlett, JG. Serologic tests for the diagnosis of HIV infection, in UpToDate. Accessed 5 October 2006.
[20] Scand J Infect Dis. 1992;24(4):419-21. Accessed 23
September 2008.
[21] Mas, A.; Soriano, V.; Gutirrez, M.; Fumanal, F.; Alonso,
A.; Gonzlez-Lahoz, J. (1997). Reliability of a new recombinant immunoblot assay (RIBA HIV-1/HIV-2 SIA)
as a supplemental (conrmatory) test for HIV-1 and HIV2 infections. Transfusion science 18 (1): 6369. PMID
10174294.
[22] Simonsen L, Bungton J, (June 1995). Multiple false
reactions in viral antibody screening assays after inuenza
vaccination. Am J Epidemiol 141 (11): 108996. PMID
7539579.
[23] Chou R, Human LH, Fu R, Smits AK, Korthuis PT (July
2005). Screening for HIV: a review of the evidence for
the U.S. Preventive Services Task Force. Ann. Intern.
Med. 143 (1): 5573. doi:10.7326/0003-4819-143-1200507050-00010. PMID 15998755.
[24] Kleinman S, Busch M, Hall L, Thomson R, Glynn S,
Gallahan D, Ownby H, Williams A (1998). Falsepositive HIV-1 test results in a low-risk screening setting of voluntary blood donation. Retrovirus Epidemiology Donor Study. JAMA 280 (12): 10805.
doi:10.1001/jama.280.12.1080. PMID 9757856.
[25] Burke D, Brundage J, Redeld R, Damato J, Schable C,
Putman P, Visintine R, Kim H (1988). Measurement
of the false positive rate in a screening program for human immunodeciency virus infections. N Engl J Med
319 (15): 9614. doi:10.1056/NEJM198810133191501.
PMID 3419477.
[26] MacDonald K, Jackson J, Bowman R, Polesky H, Rhame
F, Balfour H, Osterholm M (1989). Performance characteristics of serologic tests for human immunodeciency
virus type 1 (HIV-1) antibody among Minnesota blood
donors. Public health and clinical implications. Ann Intern Med 110 (8): 61721. doi:10.7326/0003-4819-1108-617. PMID 2648922.
[27] Busch M, Eble B, Khayam-Bashi H, Heilbron D, Murphy
E, Kwok S, Sninsky J, Perkins H, Vyas G (1991). Evaluation of screened blood donations for human immunodeciency virus type 1 infection by culture and DNA amplication of pooled cells. N Engl J Med 325 (1): 15.
doi:10.1056/NEJM199107043250101. PMID 2046708.
[28] Van de Perre P, Simonon A, Msellati P, Hitimana D,
Vaira D, Bazubagira A, Van Goethem C, Stevens A,
Karita E, Sondag-Thull D (1991). Postnatal transmission of human immunodeciency virus type 1 from
mother to infant. A prospective cohort study in Kigali, Rwanda.
N Engl J Med 325 (9): 5938.
doi:10.1056/NEJM199108293250901. PMID 1812850.
[29] Update: serologic testing for HIV-1 antibody United
States, 1988 and 1989. MMWR Morb Mortal Wkly Rep
1990; 39:380.
91
[30] Urnovitz H, Sturge J, Gottfried T (1997). Increased sensitivity of HIV-1 antibody detection. Nat Med 3 (11):
1258. doi:10.1038/nm1197-1258. PMID 9359701.
[31] Farzadegan H, Vlahov D, Solomon L, Muoz A, Astemborski J, Taylor E, Burnley A, Nelson K (1993). Detection of human immunodeciency virus type 1 infection
by polymerase chain reaction in a cohort of seronegative
intravenous drug users. J Infect Dis 168 (2): 32731.
doi:10.1093/infdis/168.2.327. PMID 8335969.
[32] https://web.archive.org/20090511203530/http:
//www.fda.gov/cber/gdlns/hivhcvnatbld.htm. Archived
from the original on 11 May 2009. Retrieved 2 November
2013. Missing or empty |title= (help)
[33] View Article. Eurosurveillance. 1 February 2005. Retrieved 2 November 2013.
[34] Defoort, J. P.; Martin, M.; Casano, B.; Prato, S.;
Camilla, C.; Fert, V. (2000). Simultaneous detection of
multiplex-amplied human immunodeciency virus type
1 RNA, hepatitis C virus RNA, and hepatitis B virus DNA
using a ow cytometer microsphere-based hybridization
assay. Journal of clinical microbiology 38 (3): 1066
1071. PMC 86341. PMID 10698998.
[35] Instruction Manual - MPCR Kit for Human Immunodeciency Virus (HIV) Type I/II, MaximBio (PDF). Retrieved 4 December 2013.
[36] Fiebig, E. W.; Wright, D. J.; Rawal, B. D.; Garrett,
P. E.; Schumacher, R. T.; Peddada, L.; Heldebrant,
C.; Smith, R.; Conrad, A.; Kleinman, S. H.; Busch,
M. P. (2003). Dynamics of HIV viremia and antibody seroconversion in plasma donors: Implications
for diagnosis and staging of primary HIV infection. AIDS (London, England) 17 (13): 18711879.
doi:10.1097/01.aids.0000076308.76477.b8.
PMID
12960819.
[37] FDA summary of branched DNA test, accessed 5 October
2006.
[38] South Africa teaching unions criticise HIV testing
in schools http://www.guardian.co.uk/world/2011/feb/
02/south-africa-hiv-testing-schools
[39] Die Burger. Die Burger. M.news24.com. Retrieved 2
November 2013.
[40] False-Positive Oral Fluid Rapid HIV Tests - New York
City, 2005-2008. Cdc.gov. Retrieved 2 November 2013.
[41] http://www.aboutmyhealth.us/oraquick.htm. Retrieved 2
November 2013. Missing or empty |title= (help)
[42] https://web.archive.org/20121214141410/http:
//www.cdc.gov/hiv/topics/testing/rapid/oral-fluid.htm.
Archived from the original on 14 December 2012.
Retrieved 2 November 2013. Missing or empty |title=
(help)
[43] Testing for HIV - Why and How | Free Testing Site
HAF. Freehivtesting.hafnyc.org. Retrieved 2 November
2013.
92
[44] https://web.archive.org/20121019035954/http:
//www.harlemunited.org/pep/testing.html.
Archived
from the original on 19 October 2012. Retrieved 2
November 2013. Missing or empty |title= (help)
[45] The scientic evidence for HIV/AIDS. AIDSTruth.org.
Retrieved 13 March 2012.
[46] The Evidence That HIV Causes AIDS. Retrieved 13
March 2012.
[47] The Controversy over HIV and AIDS. Retrieved 13
March 2012.
[48] Defective HIV Test Kit Marketer Settles FTC Charges.
Federal Trade Commission. Retrieved 5 November 2014.
Chapter 11
Prevention of HIV/AIDS
policies.
pre-exposure prophylaxis
post-exposure prophylaxis
HIV vaccines
circumcision (see also Circumcision and HIV)[1]
antiretroviral drugs to reduce viral load in the infected
condoms, and
low dead space syringes
Of these, the only universally medically proven method
for preventing the spread of HIV during sexual intercourse is the correct use of condoms, and condoms are
also the only method promoted by health authorities
worldwide. For HIV positive mothers wishing to prevent
the spread of HIV to their child during birth, antiretroviral drugs have been medically proven to reduce the likelihood of the spread of the infection. Scientists worldwide
are currently researching other prevention systems.
93
94
11.1.2
Social strategies
Each of these strategies has widely diering levels of ef- Circumcision in sub-Saharan Africa reduces the risk of
cacy, social acceptance and acceptance in the medical HIV infection in heterosexual men by between 38 perand scientic communities.
cent and 66 percent over two years.[13] Based on these
Populations which receive HIV testing are less likely to studies, the World Health Organization and UNAIDS
engage in behaviors with high risk of contracting HIV,[4] both recommended male circumcision as a method of
[14]
so HIV testing is almost always a part of any strategy to preventing female-to-male HIV transmission in 2007.
encourage people to change their behavior to become less Whether it protects against male-to-female transmission
is disputed[15][16] and whether it is of benet in developed
likely to contract HIV.
countries and among men who have sex with men is
Over 60 countries impose some form of travel restriction, undetermined.[17][18][19] For men who have sex with men
either for short or long term stays, for people infected with there is some evidence that the penetrative partner has a
HIV.[5]
lower chance of contracting HIV.[20] Some experts fear
that a lower perception of vulnerability among circumcised men may result in more sexual risk-taking behavior,
11.1.3 Advertising and campaigns
thus negating its preventive eects.[21] Women who have
female genital cutting have an increased risk
Persuasive messages delivered through health advertising undergone
[22]
of
HIV.
and social marketing campaigns which are designed to educate people about the danger of HIV/AIDS and simple
prevention strategies are also an important way of preventing HIV/AIDS. These persuasive messages have successfully increased peoples knowledges about HIV. More
importantly, information sent out through advertising and
social marketing also prove to be eective in promoting more favorable attitudes and intentions toward future
condom use even though they did not bring signicant
change in actual behaviors except those were targeting at
specic behavioral skills.[6][7]
11.1.5
95
Pre exposure
11.1.6
Post exposure
11.1.8 Mother-to-child
Programs to prevent the transmission of HIV from mothers to children can reduce rates of transmission by 9299%.[31][40] This primarily involves the use of a combination of antivirals during pregnancy and after birth
in the infant but also potentially include bottle feeding
rather than breastfeeding.[40][41] If replacement feeding
is acceptable, feasible, aordable, sustainable and safe
mothers should avoid breast-feeding their infants however exclusive breast-feeding is recommended during the
rst months of life if this is not the case.[42] If exclusive
breast feeding is carried out the provision of extended antiretroviral prophylaxis to the infant decreases the risk of
transmission.[43]
11.1.9 Vaccination
As of 2012 there is no eective vaccine for HIV or
AIDS.[44] A single trial of the vaccine RV 144 published
in 2009 found a partial ecacy rate of ~30% and has
stimulated optimism in the research community regarding developing a truly eective vaccine.[45] Further trials
of the vaccine are ongoing.[46][47]
96
2006, 48 states in the United States authorized needle ex- somehow lead to many thousands of people worldwide
change in some form or allowed the purchase of sterile becoming infected with HIV.[60] In many countries leadsyringes without a prescription at pharmacies.[51]
ers and most of the general public denied both that AIDS
were
Removal of legal barriers to operation of NEPs and other and the risk behaviors which spread HIV existed
[60]
present
outside
of
concentrated
populations.
syringe access initiatives has been identied as an important part of a comprehensive approach to reducing HIV
transmission among injection drug users (IDUs).[50] Legal barriers include both law on the books and law on
the streets, i.e., the actual practices of law enforcement
ocers,[52][53] which may or may not reect the formal
law. Changes in syringe and drug control policy can be
ineective in reducing such barriers if police continue
to treat syringe possession as a crime or participation in
NEP as evidence of criminal activity. [54] Although most
NEPs in the US are now operating legally, many report
some form of police interference.[55]
Research elsewhere has shown similar misalignment between law on the books and law on the streets. For
example, in Kyrgyzstan, although sex work, syringe sales,
and possession of syringes are not criminalized and possession of a small amount of drug has been decriminalized, gaps remain between these policies and law
enforcement knowledge and practice.[56][57][58] To optimize public health eorts targeting vulnerable groups,
law enforcement personnel and public health policies and
practices should be closely aligned. Such alignment can
be improved through policy, training, and coordination
eorts.[58]
11.1.11
Quality in Prevention
11.2 History
11.2.1
1980s
The Centers for Disease Control was the rst organization to recognize the pandemic which came to be called
AIDS.[60] Their announcement came on June 5, 1981
when one of their journals published an article reporting ve cases of pneumonia caused by Pneumocystis
jirovecii, all in gay men living in Los Angeles.[61][62]
In May 1983, scientists isolated a retrovirus which was
later called HIV from an AIDS patient in France.[63] At
this point the disease caused AIDS was proposed to be
caused by HIV, and people began to consider prevention
of HIV as a strategy for preventing AIDS.
In 2001 the United States began a War in Afghanistan related to ghting the Taliban. The Taliban, however, had
opposed local opium growers and the heroin trade; when
the government of Afghanistan fell during the war, opium
production was unchecked. By 2003, the world market
In the 1980s public policy makers and most of the pub- saw an increase in the available heroin supply, and in forlic could not understand that the overlap of sexual and mer Soviet states especially, there was an increase in HIV
needle-sharing networks with the general community had infection due to injection drug use. Eorts were renewed
97
Since HIV-1 is never cleared by the immune system, removal of the virus is required in order to cure the disease.
The same technique could theoretically be used against a
variety of viruses. The research shows that these molecu11.2.3 From 2011
lar tools also hold promise as a therapeutic vaccine; cells
armed with the nuclease-RNA combination proved imIn July 2011, it was announced by the WHO and UNpervious to HIV infection.
AIDS that a once-daily antiretroviral tablet could significantly reduce the risk of HIV transmission in heterosexual couples.[79] These ndings were based on the results of two trials conducted in Kenya and Uganda, and 11.3 See also
Botswana.
Relationship between education and HIV/AIDS
The Partners PrEP (pre-exposure prophylaxis) trial was
funded by the Bill and Melinda Gates Foundation[80] and
AIDS education and training centers
conducted by the International Clinical Research Center
TeachAIDS
at the University of Washington. The trial followed 4758
heterosexual couples in Kenya and Uganda, in which
one individual was HIV positive and the other was HIV
negative.[79] The uninfected (HIV negative) partner was
given either a once-daily tenofovir tablet, a once-daily
combination tablet of tenofovir and emtricitabine, or a
placebo tablet containing no antiretroviral drug. These
couples also received counselling and had access to free
male and female condoms. In couples taking tenofovir
and tenofovir/emtricitabine, there was a 62% and 73%
decrease, respectively, in the number of HIV infections as
compared to couples who were receiving the placebo.[79]
A similar result was observed with the TDF2 trial, conducted by the United States Centers for Disease Control
in partnership with the Botswana Ministry of Health.[81]
The trial followed 1200 HIV negative men and women
in Francistown, Botswana, a city known to have one of
the worlds highest HIV infection rates.[81] Participants
received either a once-daily tenofovir/emtricitabine combination tablet or a placebo. In those taking the antiretroviral treatment, there was found to be a 63% decrease in
the risk of acquiring HIV, as compared to those receiving
the placebo.[79]
The HIV-1 virus has proved to be tenacious, inserting its
genome permanently into victims DNA, forcing patients
to take a lifelong drug regimen to control the virus and
prevent a fresh attack. Now, a team of Temple University
School of Medicine researchers have designed a way to
snip out the integrated HIV-1 genes for good.
This is one important step on the path toward a permanent cure for AIDS. This is the rst successful attempt to
eliminate latent HIV-1 virus from human cells.
11.4 References
[1] Nandra, Iqbal (28 March 2008). WHO and UNAIDS
announce recommendations from expert consultation on
male circumcision for HIV prevention. who.int. Retrieved 3 July 2011.
[2] Holly Richmond (18 September 2013). Everybody
wants condom vending machines. Grist Magazine. Grist
Magazine, Inc. Retrieved 19 September 2013.
[3] Club 25 Pledge
[4] Weinhardt LS, Carey MP, Johnson BT, Bickham NL
(1999). Eects of HIV counseling and testing on sexual risk behavior: a meta-analytic review of published research, 1985-1997. American Journal of Public Health
89 (9): 13971405. doi:10.2105/ajph.89.9.1397.
[5] HIVTravel - Regulations on Entry, Stay, and Residence
for PLHIV. Retrieved 2012-02-26.
[6] Albarracin, D.; McNatt, P. S.; Klein, C. T. F.; Ho, R. M.;
Mitchell, A. L.; Kumkale, G. T. (2003). Persuasive communications to change actions: An analysis of behavioral
and cognitive impact in HIV prevention. Health Psychology 22: 166177. doi:10.1037/0278-6133.22.2.166.
[7] Albarracin, D.; Gillette, J. C.; Earl, A.; Glasman, L. R.;
Durantini, M. R.; Ho, M-H (2005). A test of major assumptions about behavior change: A comprehensive look
at the eects of passive and active HIV-prevention interventions since the beginning of the epidemic. Psychological Bulletin 131: 856897. doi:10.1037/00332909.131.6.856.
98
[11] Baptista, M; Ramalho-Santos, J (2009-11-01). Spermicides, microbicides and antiviral agents: recent advances in the development of novel multi-functional compounds.. Mini reviews in medicinal chemistry 9 (13):
155667. doi:10.2174/138955709790361548. PMID
20205637.
[12] Celum,
C; Baeten,
JM (February 2012).
Tenofovir-based
pre-exposure
prophylaxis
for
HIV prevention:
evolving evidence..
Current
Opinion in Infectious Diseases 25 (1):
517.
doi:10.1097/QCO.0b013e32834ef5ef. PMC 3266126.
PMID 22156901.
[13] Siegfried, N; Muller, M; Deeks, JJ; Volmink, J
(2009-04-15). Male circumcision for prevention of
heterosexual acquisition of HIV in men.. Cochrane
database of systematic reviews (Online) (2): CD003362.
doi:10.1002/14651858.CD003362.pub2.
PMID
19370585.
[14] WHO and UNAIDS announce recommendations from
expert consultation on male circumcision for HIV prevention. World Health Organization. Mar 28, 2007.
[15] Larke, N (2010 May 27 Jun 9). Male circumcision, HIV and sexually transmitted infections: a review.
British journal of nursing (Mark Allen Publishing) 19 (10):
62934. doi:10.12968/bjon.2010.19.10.48201. PMID
20622758. Check date values in: |date= (help)
[16] Eaton, L; Kalichman, SC (November 2009). Behavioral
aspects of male circumcision for the prevention of HIV
infection. Current HIV/AIDS reports 6 (4): 18793.
doi:10.1007/s11904-009-0025-9. PMC 3557929. PMID
19849961.
[17] Kim, HH; Li, PS, Goldstein, M (November
2010).
Male circumcision:
Africa and beyond?". Current Opinion in Urology 20 (6): 515
9.
doi:10.1097/MOU.0b013e32833f1b21.
PMID
20844437.
[18] Templeton, DJ; Millett, GA, Grulich, AE (February
2010). Male circumcision to reduce the risk of HIV and
sexually transmitted infections among men who have sex
with men. Current Opinion in Infectious Diseases 23 (1):
4552. doi:10.1097/QCO.0b013e328334e54d. PMID
19935420.
[19] Wiysonge, CS.; Kongnyuy, EJ.; Shey, M.; Muula,
AS.; Navti, OB.; Akl, EA.; Lo, YR. (2011).
Wiysonge, Charles Shey, ed.
Male circumcision
for prevention of homosexual acquisition of HIV in
men. Cochrane Database Syst Rev (6): CD007496.
doi:10.1002/14651858.CD007496.pub2.
PMID
21678366.
[20] http://www.afao.org.au/library/hiv-australia/volume-9/
number-3/hiv-prevention-and-anal-sex
[21] Eaton LA, Kalichman S (December 2007). Risk compensation in HIV prevention: implications for vaccines, microbicides, and other biomedical HIV prevention technologies. Curr HIV/AIDS Rep 4 (4): 16572.
doi:10.1007/s11904-007-0024-7. PMC 2937204. PMID
18366947.
[22] Utz-Billing I, Kentenich H (December 2008). Female genital mutilation: an injury, physical and mental
harm. J Psychosom Obstet Gynaecol 29 (4): 2259.
doi:10.1080/01674820802547087. PMID 19065392.
[23] Underhill K, Operario D, Montgomery P (2008). Operario, Don, ed. Abstinence-only programs for HIV
infection prevention in high-income countries. Cochrane
Database of Systematic Reviews (4): CD005421.
doi:10.1002/14651858.CD005421.pub2.
PMID
17943855.
[24] Tolli, MV (2012-05-28).
Eectiveness of peer
education interventions for HIV prevention, adolescent pregnancy prevention and sexual health promotion for young people: a systematic review of European studies.. Health education research 27: 904913.
doi:10.1093/her/cys055. PMID 22641791.
[25] Ljubojevi, S; Lipozeni, J (2010). Sexually transmitted infections and adolescence.. Acta dermatovenerologica Croatica : ADC 18 (4): 30510. PMID 21251451.
[26] Patel VL, Yoskowitz NA, Kaufman DR, Shortlie EH
(2008). Discerning patterns of human immunodeciency virus risk in healthy young adults. Am J Med
121 (4): 758764. doi:10.1016/j.amjmed.2008.04.022.
PMC 2597652. PMID 18724961.
[27] Ng, BE; Butler, LM; Horvath, T; Rutherford, GW
(2011-03-16).
Population-based biomedical sexually transmitted infection control interventions
for reducing HIV infection..
Cochrane database
of systematic reviews (Online) (3):
CD001220.
doi:10.1002/14651858.CD001220.pub3.
PMID
21412869.
[28] National Institute of Allergy and Infectious Diseases (NIAID), Treating HIV-infected People with Antiretrovirals
Protects Partners from Infection, NIH News, 2011 May
[29] Anglemyer, A; Rutherford, GW; Baggaley, RC;
Egger, M; Siegfried, N (2011-08-10). Antiretroviral therapy for prevention of HIV transmission
in HIV-discordant couples..
Cochrane database
of systematic reviews (Online) (8):
CD009153.
doi:10.1002/14651858.CD009153.pub2.
PMID
21833973.
[30] Centers for Disease Control (CDC) (August 1987).
Recommendations for prevention of HIV transmission
in health-care settings. MMWR 36 (Suppl 2): 1S18S.
PMID 3112554.
[31] Kurth, AE; Celum, C; Baeten, JM; Vermund, SH;
Wasserheit, JN (March 2011). Combination HIV
prevention: signicance, challenges, and opportuniCurrent HIV/AIDS reports 8 (1): 6272.
ties..
doi:10.1007/s11904-010-0063-3. PMC 3036787. PMID
20941553.
[32] World Health Organization. Eectiveness of Sterile Needle and Syringe Programming in Reducing
HIV/AIDS Among Injecting Drug Users (PDF). Evidence for Action Technical Papers. Retrieved 7 January
2012.
11.4. REFERENCES
99
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[45] Reynell, L; Trkola, A (2012-03-02). HIV vaccines: an
attainable goal?". Swiss medical weekly 142: w13535.
doi:10.4414/smw.2012.13535. PMID 22389197.
[35] Emma Bourke (14 June 2013). Preventive drug could reduce HIV transmission among injecting drug users. The
Conversation Australia. The Conversation Media Group.
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[48] Case P, Meehan T, Jones TS (1998). Arrests and incarceration of injection drug users for syringe possession in Massachusetts: implications for HIV prevention.
J. Acquir. Immune Dec. Syndr. Hum. Retrovirol.
18 Suppl 1: S715. doi:10.1097/00042560-19980200100013. PMID 9663627.
[37] Young, TN; Arens, FJ; Kennedy, GE; Laurie, JW; Rutherford, G (2007-01-24). Antiretroviral post-exposure
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Cochrane database of systematic reviews (Online) (1):
CD002835.
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PMID 17253483.
[38] Kripke, C (2007-08-01). Antiretroviral prophylaxis for
occupational exposure to HIV.. American family physician 76 (3): 3756. PMID 17708137.
[39] Desai, Monica; Woodhall, Sarah C; Nardone, Anthony; Burns, Fiona; Mercey, Danielle; Gilson, Richard
(2015). Active recall to increase HIV and STI testing: a systematic review. Sexually Transmitted Infections: sextrans2014051930. doi:10.1136/sextrans2014-051930. ISSN 1368-4973.
[40] Coutsoudis, A; Kwaan, L; Thomson, M (October 2010).
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(10): 116375. doi:10.1586/eri.10.94. PMID 20954881.
[41] Siegfried, N; van der Merwe, L; Brocklehurst, P; Sint,
TT (2011-07-06). Antiretrovirals for reducing the
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CD003510.
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PMID 21735394.
100
101
Chapter 12
Management of HIV/AIDS
HAART redirects here. For UK estate agency Haart, several more NRTIs were developed but even in combisee Spicerhaart.
nation were unable to suppress the virus for long periods of time and patients still inevitably died.[7] To disThe management of HIV/AIDS normally includes the tinguish from this early anti-retroviral therapy (ART),
the term highly active anti-retroviral therapy (HAART)
use of multiple antiretroviral drugs in an attempt to control HIV infection. There are several classes of antiretro- was introduced. In 1996 by sequential publications in
The New England Journal of Medicine by Hammer and
viral agents that act on dierent stages of the HIV life[8]
[9]
cycle. The use of multiple drugs that act on dierent colleagues and Gulick and coinvestigators illustrating the substantial benet of combining 2 NRTIs with a
viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patients total bur- new class of anti-retrovirals, protease inhibitors, namely
den of HIV, maintains function of the immune system, indinavir. This concept of 3-drug therapy was quickly inand prevents opportunistic infections that often lead to corporated into clinical practice and rapidly showed impressive benet with a 60% to 80% decline in rates of
death.[1]
AIDS, death, and hospitalization.[1]
Treatment has been so successful that in many parts of
the world, HIV has become a chronic condition in which
progression to AIDS is increasingly rare. Anthony Fauci,
head of the United States National Institute of Allergy 12.2 Classes of drugs
and Infectious Diseases, has written, With collective
and resolute action now and a steadfast commitment for
years to come, an AIDS-free generation is indeed within
reach. In the same paper, he noted that an estimated
700,000 lives were saved in 2010 alone by antiretroviral therapy.[2] As another commentary in The Lancet
noted, Rather than dealing with acute and potentially
life-threatening complications, clinicians are now confronted with managing a chronic disease that in the absence of a cure will persist for many decades.[3]
The United States Department of Health and Human
Services and the World Health Organization[4] recommend oering antiretroviral treatment to all patients with
HIV.[5] Because of the complexity of selecting and following a regimen, the potential for side eects, and the
importance of taking medications regularly to prevent Schematic description of the mechanism of the four classes of
viral resistance, such organizations emphasize the impor- currently available antiretroviral drugs against HIV
tance of involving patients in therapy choices and recommend analyzing the risks and the potential benets.[5]
There are ve classes of drugs, which are usually used
in combination, to treat HIV infection. Use of these
drugs in combination can be termed anti-retroviral therapy (ART), combination anti-retroviral therapy (cART)
12.1 History
or highly active anti-retroviral therapy (HAART). Antiretroviral (ARV) drugs are broadly classied by the phase
The rst eective therapy against HIV was the nucleoside of the retrovirus life-cycle that the drug inhibits. Typireverse transcriptase inhibitor (NRTI) zidovudine (AZT). cal combinations include 2 NRTIs as a backbone along
It was approved by the US FDA in 1987.[6] Subsequently with 1 NNRTI, PI or INSTI as a base.[5]
102
103
currently under clinical trial, and raltegravir became
the rst to receive FDA approval in October 2007.
Raltegravir has two metal binding groups that compete for substrate with two Mg2+ ions at the metal
binding site of integrase. As of early 2014, two
other clinically approved integrase inhibitors are
elvitegravir and dolutegravir.[14]
Protease inhibitors block the viral protease enzyme necessary to produce mature virions upon
budding from the host membrane. Particularly,
these drugs prevent the cleavage of gag and gag/pol
precursor proteins.[15] Virus particles produced
in the presence of protease inhibitors are defective and mostly non-infectious. Examples of
HIV protease inhibitors are Lopinavir, Indinavir,
Nelnavir, Amprenavir and Ritonavir. Darunavir
and atazanavir are currently recommended as rst
line therapy choices.[5] Maturation inhibitors have a
similar eect by binding to gag, but development of
two experimental drugs in this class, Bevirimat and
Vivecon, was halted in 2010.[16] Resistance to some
protease inhibitors is high. Second generation drugs
have been developed that are eective against otherwise resistant HIV variants.[15]
104
174 (5): 9628. doi:10.1093/infdis/174.5.962. PMID In April 1995, Merck and the National Institute of Al8896496.</ref>
lergy and Infectious Diseases began recruiting patients
Antiretroviral combination therapy defends against resis- for a trial examining the eects of a three drug combinaprotease inhibitor indinavir and two nucleoside
tance by suppressing HIV replication as much as possible, tion of the
[9]
analogs.
illustrating the substantial benet of combinthus reducing the potential pool of spontaneous resistance
ing
2
NRTIs
with a new class of anti-retrovirals, protease
[18]
mutations.
inhibitors, namely indinavir. Later that year David Ho
Combinations of antiretrovirals create multiple obstacles became an advocate of this hit hard, hit early approach
to HIV replication to keep the number of ospring low with aggressive treatment with multiple antiretrovirals
and reduce the possibility of a superior mutation. If a early in the course of the infection.[27] Later reviews in
mutation that conveys resistance to one of the drugs be- the late 90s and early 2000s noted that this approach of
ing taken arises, the other drugs continue to suppress re- hit hard, hit early ran signicant risks of increasing
production of that mutation. With rare exceptions, no side eects and development of multidrug resistance, and
individual antiretroviral drug has been demonstrated to this approach was largely abandoned. The only consensus
suppress an HIV infection for long; these agents must be was on treating patients with advanced immunosupprestaken in combinations in order to have a lasting eect. sion (CD4 counts less than 350/L).[28] Treatment with
As a result, the standard of care is to use combinations antiretrovirals was expensive at the time, ranging from
of antiretroviral drugs.[5] Combinations usually consist $10,000 to $15,000 a year.[29]
of three drugs from at least two dierent classes.[5] This
three drug combination is commonly known as a triple The timing of when to start therapy has continued to
cocktail.[19] Combinations of antiretrovirals are subject be a core controversy within the medical community,
studies have led to more clarity. The NAto positive and negative synergies, which limits the num- though recent
[30]
ACCORD
study observed patients who started anber of useful combinations.
tiretroviral therapy either at a CD4 count of less than 500
In recent years, drug companies have worked together to versus less than 350 and showed that patients who started
combine these complex regimens into simpler formulas, ART at lower CD4 counts had a 69% increase in the risk
termed xed-dose combinations.[20] For instance, there of death.[31] In 2015 the START[32] and TEMPRANO[33]
are now several options that combine 3 drugs into one studies both showed that patients lived longer if they
pill taken once daily.[21][22][23] This greatly increases the started antiretrovirals at the time of their diagnosis, rather
ease with which they can be taken, which in turn in- than waiting for their CD4 counts to drop to a specied
creases the consistency with which medication is taken level.
(adherence),[24] and thus their eectiveness over the longterm. Not taking anti-retrovirals regularly is a cause of Other arguments for starting therapy earlier are that peoshown to have less
resistance development in people who have started tak- ple who start therapy later have been
[34]
recovery
of
their
immune
systems,
and higher CD4
[25]
ing them previously.
Patients who take medications
[35]
counts
are
associated
with
less
cancer.
regularly can stay on one regimen without developing
resistance.[25] This greatly increases life expectancy and
leaves more drugs available to the individual should the Treatment as prevention
need arise.
12.3.1
Fixed-dose combinations
105
therapy on the basis of clinical and/or psychosocial
factors.
12.4.2
Guideline Sources
Baseline resistance
Baseline resistance is the presence of resistance mutations in patients who have never been treated before for
HIV. In countries with a high rate of baseline resistance,
resistance testing is recommended before starting treatment; or, if the initiation of treatment is urgent, then a
best guess treatment regimen should be started, which
is then modied on the basis of resistance testing.[13]
In the UK, there is 11.8% medium to high-level resistance at baseline to the combination of efavirenz + zidovudine + lamivudine, and 6.4% medium to high level
resistance to stavudine + lamivudine + nevirapine.[46]
In the US, 10.8% of one cohort of patients who had
never been on ART before had at least one resistance
mutation in 2005.[47] Various surveys in dierent parts
of the world have shown increasing or stable rates of
baseline resistance as the era of eective HIV therapy
continues.[48][49][50][51] With baseline resistance testing,
a combination of antiretrovirals that are likely to be effective can be customized for each patient.
For resource limited countries, most national guidelines closely follow the World Health Organization
12.4.3
guidelines.[4]
Regimens
ART also is recommended for HIV-infected individuals for the prevention of transmission of HIV.
Patients starting ART should be willing and able
to commit to treatment and understand the benets
and risks of therapy and the importance of adherence. Patients may choose to postpone therapy, and
providers, on a case-by-case basis, may elect to defer
106
In the case of the protease inhibitor based regimens, ritonavir is used at low doses to inhibit cytochrome p450
enzymes and boost the levels of other protease inhibitors, rather than for its direct antiviral eect. This
boosting eect allows them to be taken less frequently
throughout the day.[52] Cobicistat is used with elvitegravir
for a similar eect but does not have any direct antiviral
eect itself.[53]
12.4.4
Special populations
Acute infection
In the rst 6 months after infection HIV viral loads tend
to be elevated and people are more often symptomatic
than in later latent phases of HIV disease. There may
be special benets to starting antiretroviral therapy early
during this acute phase, including lowering the viral setpoint or baseline viral load, reduce the mutation rate of
the virus, and reduce the size of the viral reservoir (See
section below on viral reservoirs).[5] The SPARTAC trial
compared 48 weeks of ART vs 12 weeks vs no treatment
in acute HIV infection and found that 48 weeks of treatment delayed the time to decline in CD4 count below
350 cells per ml by 65 weeks and kept viral loads significantly lower even after treatment was stopped.[54] Since
viral loads are usually very high during acute infection,
this period carries an estimated 26 times higher risk of
transmission.[55] By treating acutely infected patients, it
is presumed that it could have a signicant impact on decreasing overall HIV transmission rates since lower viral
loads are associated with lower risk of transmission (See
section on treatment as prevention). However an overall benet has not been proven and has to be balanced
with the risks of HIV treatment. Therapy during acute
infection carries a grade BII recommendation from the
US DHHS.[5]
Children
HIV can be especially harmful to infants and children,
with one study in Africa showing that 52% of untreated
children born with HIV had died by age 2.[56] By ve
years old, the risk of disease and death from HIV starts
to approach that of young adults. The WHO recommends treating all children less than 5 years old, and
starting all children older than 5 with stage 3 or 4 disease or CD4 <500 cells/ml.[41] DHHS guidelines are
more complicated but recommend starting all children
less than 12 months old and children of any age who have
symptoms.[57]
107
balances the low risk of transmission through breast feed- 12.6 Response to therapy
ing from women who are on ART with the benets of
breastfeeding against diarrhea, prneumonia and malnutrition. It also strongly recommends that breastfeeding in- 12.6.1 Virologic response
fants receive prophylactic ART.[41] In the US, the DHHS
recommends against women with HIV breastfeeding.[63] Suppressing the viral load to undetectable levels (<50
copies per ml) is the primary goal of ART.[52] This
should happen by 24 weeks after starting combination
Older adults
therapy.[44] Viral load monitoring is the most important
predictor of response to treatment with ART.[79] Levels
With improvements in HIV therapy, several studies now higher than 200 copies per ml is considered virologic failestimate that patients on treatment in high-income coun- ure, and should prompt further testing for potential viral
tries can expect a normal life expectancy.[66][67] This resistance.[5] Lack of viral load suppression on ART is
means that a higher proportion of people living with HIV termed virologic failure.
are now older and research is ongoing into the unique aspects of HIV infection in the older adult. There is data
that older people with HIV have a blunted CD4 response
to therapy but are more likely to achieve undetectable vi- 12.6.2 Immunologic response
ral levels.[68] However, not all studies have seen a difference in response to therapy.[69] Current guidelines do CD4 cell counts are another key measure of immune stanot have separate treatment recommendations for older tus and ART eectiveness.[44] CD4 counts should rise 50
adults, but it is important to take into account that older to 100 cells per ml in the rst year of therapy.[52] There
patients are more likely to be on multiple non-HIV med- can be substantial uctuation in CD4 counts of up to 25%
ications and consider drug interactions with any poten- based on the time of day or concominant infections.[80]
tial HIV medications.[70] There are also increased rates In one long term study, the majority of increase in CD4
of HIV associated non-AIDS conditions (HANA) such cell counts was in the rst two years after starting ART
as heart disease, liver disease and dementia that are mul- with little increase afterwards. This study also found that
tifactorial complications from HIV, associated behaviors, patients who began ART at lower CD4 counts contincoinfections like hepatitis B, hepatitis C, and human pa- ued to have lower CD4 counts than those who started at
pilloma virus (HPV) as well as HIV treatment.[70]
higher CD4 counts.[81] When viral suppression on ART
is achieved but without a corresponding increase in CD4
counts it can be termed immunologic nonresponse or immunologic failure. While this is predictive of worse out12.5 Concerns
comes, there is no consensus on how to adjust therapy
There are several concerns about antiretroviral regimens to immunologic failure and whether switching therapy is
benecial. DHHS guidelines do not recommend switchthat should be addressed before initiating:
ing an otherwise suppressive regimen.[5][82]
Intolerance: The drugs can have serious side-eects
which can lead to harm as well as keep patients from
taking their medications regularly.
108
12.9.1
NRTIs
The NRTIs can interfere with mitochondrial DNA synthesis and lead to high levels of lactate and lactic acidosis, liver steatosis, peripheral neuropathy, myopathy and
lipoatrophy.[52] Current rst line NRTIs such as lamivudine/emtrictabine, tenofovir, and abacavir are less likely
to cause mitochondrial dysfunction.[85][86]
12.9.2
NNRTIs
12.9.3
Protease inhibitors
12.9.4
Integrase inhibitors
Women with HIV have been shown to have decreased fertility which can aect available reproductive options.[94]
In cases where the woman is HIV negative and the man is
HIV positive, the primary assisted reproductive method
used to prevent HIV transmission is sperm washing followed by intrauterine insemination (IUI) or in vitro fertilization (IVF). Preferably this is done after the man
has achieved an undetectable plasma viral load.[95] In
the past there have been cases of HIV transmission
to an HIV-negative partner through processed articial
insemination,[96] but a large modern series in which followed 741 couples where the man had a stable viral load
and semen samples were tested for HIV-1, there were no
cases of HIV transmission.[97]
For cases where the woman is HIV positive and the man
is HIV negative, the usual method is articial insemination.[95] With appropriate treatment the risk of motherto-child infection can be reduced to below 1%.[98]
12.12.1
Berlin patient
12.12.2
Viral reservoirs
109
12.14 References
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October 1, 1999. doi:10.1097/00002030-19991001000017. PMID 10513653.
[2] Fauci, AS (25 July 2012). Toward an AIDS-free generation. JAMA 308 (4): 343. doi:10.1001/jama.2012.8142.
[3] Deeks, Steven G (8 November 2013).
The end
of AIDS: HIV infection as a chronic disease. The
Lancet 382 (9903): 15251533. doi:10.1016/S01406736(13)61809-7.
[4] Guidelines: HIV. World Health Organization. Retrieved 2015-10-27.
[5] Guidelines for the Use of Antiretroviral Agents in HIV1-Infected Adults and Adolescents (PDF). US Department of Health and Human Services. 2015-04-08.
[6] U.S Approves Drug to Prolong Lives of AIDS Patients.
New York Times. 1987-03-21.
[7] Natural History of Opportunistic Disease in an HIVInfected Urban Clinical Cohort. Annals of Internal
Medicine 124 (7): 633. doi:10.7326/0003-4819-124-7199604010-00003.
[8] A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeciency virus infection and CD4 cell counts of 200 per cubic millimeter
110
[24] Fixed-dose combinations improve medication compliance: a meta-analysis. Am. J. Med. 120 (8): 7139. August 2007. doi:10.1016/j.amjmed.2006.08.033. PMID
17679131.
[25] Adherence-resistance relationships to combination HIV
antiretroviral therapy.. Curr HIV/AIDS Rep 4 (2): 65
72. May 2007. doi:10.1007/s11904-007-0010-0. PMID
17547827.
[26] Darbyshire, J (1995). Perspectives in drug therapy of
HIV infection. Drugs. 49 Suppl 1 (Supplement 1): 1
3; discussion 3840. doi:10.2165/00003495-19950049100003. PMID 7614897.
[27] Ho, DD (1995). Time to hit HIV, early and hard.
The New England Journal of Medicine 333 (7): 4501.
doi:10.1056/NEJM199508173330710. PMID 7616996.
[28] Harrington, M; Carpenter, CC (2000). Hit HIV-1
hard, but only when necessary. The Lancet 355 (9221):
214752. doi:10.1016/S0140-6736(00)02388-6. PMID
10902643.
[29] Sonenklar, C (2011). Chapter 6: Treatment for HIV
and AIDS. AIDS. USA Today Health Reports: Diseases
and Disorders. Minneapolis, MN: Twenty-First Century
Books. pp. 90101. ISBN 9780822585817.
[30] Kitahata, Mari M.; Gange, Stephen J.; Abraham, Alison G.; Merriman, Barry; Saag, Michael S.; Justice,
Amy C.; Hogg, Robert S.; Deeks, Steven G.; Eron,
Joseph J. (2009-04-30). Eect of early versus deferred antiretroviral therapy for HIV on survival. The
New England Journal of Medicine 360 (18): 18151826.
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[31] Eect of early versus deferred antiretroviral therapy for HIV on survival.. New England Journal of
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doi:10.1056/NEJMoa0807252.
[32] Initiation of Antiretroviral Therapy in Early
Asymptomatic HIV Infection. New England Journal of Medicine 373 (9): 795807.
2015-08-27.
doi:10.1056/NEJMoa1506816. ISSN 0028-4793. PMC
4569751. PMID 26192873.
[33] Danel, Christine; Moh, Raoul; Gabillard, Delphine;
Badje, Anani; Le Carrou, Jrme; Ouassa, Timothe;
Ouattara, Eric; Anzian, Amani (2015-08-27). A Trial
of Early Antiretrovirals and Isoniazid Preventive Therapy
in Africa. The New England Journal of Medicine 373 (9):
808822. doi:10.1056/NEJMoa1507198. ISSN 15334406. PMID 26193126. Missing |last1= in Authors list
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[34] Incomplete Peripheral CD4+ Cell Count Restoration in
HIV-Infected Patients Receiving Long-Term Antiretroviral Treatment. Clinical Infectious Diseases 48 (6): 787
794. 2009-03-15. doi:10.1086/597093.
[35] HIV-induced immunodeciency and mortality from
AIDS-dening and non-AIDS-dening malignancies. AIDS 22 (16): 21432153. Oct 18, 2008.
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[41] WHO | Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. June
30, 2013. p. 38. ISBN 978 92 4 150572 7.
[42] CD4+ CountGuided Interruption of Antiretroviral
Treatment. New England Journal of Medicine 355 (22):
22832296. 2006. doi:10.1056/NEJMoa062360.
[56] Mortality of infected and uninfected infants born to HIVinfected mothers in Africa: a pooled analysis. The
Lancet 364 (9441): 12361243. October 8, 2004.
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[57] Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection (PDF). US Department of Health
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Transmission. NEJM 341 (6): 394402. 1999.
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[62] Mother-to-Child Transmission of HIV Infection in the
Era of Highly Active Antiretroviral Therapy. Clin Infect
Dis. 40 (3): 458465. 02/01/2005. doi:10.1086/427287.
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[63] Recommendations for Use of Antiretroviral Drugs in
Pregnant HIV-1-Infected Women for Maternal Health
and Interventions to Reduce Perinatal HIV Transmission
in the United States (PDF). US DHHS. March 28, 2014.
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[64] Mother-to-Child Transmission of HIV Infection in the
Era of Highly Active Antiretroviral Therapy. Clin Infect
Dis 40 (3): 458465. 02/01/2005. doi:10.1086/427287.
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[65] Longitudinal analysis of human immunodeciency virus
type 1 RNA in breast milk and of its relationship to
infant infection and maternal disease. The Journal of
infectious diseases 187 (5): 741747. Mar 1, 2003.
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[66] Impact on life expectancy of HIV-1 positive individuals
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[67] Life expectancy living with HIV: recent estimates and future implications..
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[68] Older age and the response to and tolerability of antiretroviral therapy. Arch Intern Med 167 (7): 684. April
9, 2007. doi:10.1001/archinte.167.7.684.
[69] Virologic and immunologic response to HAART, by age
and regimen class. AIDS 24 (16): 24692479. October
2010. doi:10.1097/QAD.0b013e32833e6d14.
[70] Management of human immunodeciency virus infection in advanced age. JAMA 309 (13): 1397. April 3,
2013. doi:10.1001/jama.2013.2963.
[71] Antiretroviral medication adherence and the development of class-specic antiretroviral resistance. AIDS 23 (9): 10351046. Jun 1, 2009.
doi:10.1097/QAD.0b013e32832ba8ec.
[72] Global Price Reporting Mechanism for HIV, tuberculosis and malaria. World Health Organization. Retrieved
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[73] Antiretroviral Drug Prices. Avert. Retrieved 2014-0412.
[74] New one-pill, $10-per-month anti-retroviral AIDS treatment debuts in South Africa. The Raw Story. Agence
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113
Chapter 13
Epidemiology of HIV/AIDS
HIV/AIDS is a global pandemic.[1] As of 2012, approximately 35.3 million people are living with HIV
globally.[2] Of these, approximately 17.2 million are men,
16.8 million are women and 3.4 million are less than 15
years old.[3] There were about 1.8 million deaths from
AIDS in 2010, down from 2.2 million in 2005.[3]
Sub-Saharan Africa is the region most aected. In 2010,
an estimated 68% (22.9 million) of all HIV cases and
66% of all deaths (1.2 million) occurred in this region.[4]
This means that about 5% of the adult population in
this area is infected.[5] Here, in contrast to other regions,
women compose nearly 60% of cases.[4] South Africa has
the largest population of people with HIV of any country
in the world, at 5.9 million.[4]
13.1 By region
See also: List of countries by HIV/AIDS adult prevalence
rate
114
13.1. BY REGION
115
40
Botswana
South Africa
Kenya
60
Swaziland
50
Uganda
Zimbabwe
Sub-Saharan Africa
30
20
13.1.1
Sub-Saharan Africa
10
0
1960
1970
1980
1990
2000
2010
Graphs of life expectancy at birth for some sub-Saharan countries showing the fall in the 1990s primarily due to the AIDS
pandemic.[14]
less aected by the pandemic. Several countries reportedly have prevalence rates around 2 to 3%, and no country
has rates above 10%. In Nigeria and Cte d'Ivoire, two
of the regions most populous countries, between 5 and
7% of adults are reported to carry the virus.
Across Sub-Saharan Africa, more women are infected
with HIV than men, with 13 women infected for every
10 infected men. This gender gap continues to grow.
Throughout the region, women are being infected with
HIV at earlier ages than men. The dierences in infecEstimated HIV infection in Africa in 2011.
tion levels between women and men are most pronounced
among young people (aged 1524 years). In this age
group, there are 36 women infected with HIV for every
Main article: HIV/AIDS in Africa
10 men. The widespread prevalence of sexually transmitted
diseases, the practice of scarication, unsafe blood
Sub-Saharan Africa remains the hardest-hit region. HIV
transfusions,
and the poor state of hygiene and nutrition
infection is becoming endemic in sub-Saharan Africa,
in
some
areas
may all be facilitating factors in the transwhich is home to just over 12% of the worlds populamission
of
HIV-1
(Bentwich et al., 1995).
[12]
tion but two-thirds of all people infected with HIV.
The adult HIV prevalence rate is 5.0% and between 21.6 Mother-to-child transmission is another contributing facmillion and 24.1 million total are aected.[12] However, tor in the transmission of HIV-1 in developing nations.
the actual prevalence varies between regions. Presently, Due to a lack of testing, a shortage in antenatal theraSouthern Africa is the hardest hit region, with adult preva- pies and through the feeding of contaminated breast milk,
lence rates exceeding 20% in most countries in the region, 590,000 infants born in developing countries are infected
and 30% in Swaziland and Botswana.
with HIV-1 per year. In 2000, the World Health OrganiEastern Africa also experiences relatively high levels of zation estimated that 25% of the units of blood transfused
prevalence with estimates above 10% in some countries, in Africa were not tested for HIV, and that 10% of HIV
although there are signs that the pandemic is declining in infections in Africa were transmitted via blood.
this region. West Africa on the other hand has been much Poor economic conditions (leading to the use of dirty nee-
116
dles in healthcare clinics) and lack of sex education contribute to high rates of infection. In some African countries, 25% or more of the working adult population is
HIV-positive. Poor economic conditions caused by slow
onset-emergencies, such as drought, or rapid onset natural disasters and conict can result in young women and
girls being forced into using sex as a survival strategy.[15]
Worse still, research indicates that as emergencies, such
as drought, take their toll and the number of potential
'clients decreases, women are forced by clients to accept
greater risks, such as not using contraceptives.[15]
AIDS-denialist policies have impeded the creation of effective programs for distribution of antiretroviral drugs.
Denialist policies by former South African President
Thabo Mbeki's administration led to several hundred
thousand unnecessary deaths.[16][17] UNAIDS estimates
that in 2005 there were 5.5 million people in South Africa
infected with HIV 12.4% of the population. This was Migrants, in particular, are vulnerable and 67% of those
an increase of 200,000 people since 2003.
infected in Bangladesh and 41% in Nepal are migrants reAlthough HIV infection rates are much lower in Nigeria turning from India.[20] This is in part due to human trafthan in other African countries, the size of Nigerias pop- cking and exploitation, but also because even those miulation meant that by the end of 2003, there were an es- grants who willingly go to India in search of work are oftimated 3.6 million people infected. On the other hand, ten afraid to access state health services due to concerns
Uganda, Zambia, Senegal, and most recently Botswana over their immigration status.[20]
have begun intervention and educational measures to slow
the spread of HIV, and Uganda has succeeded in actually
13.1.4 East Asia
reducing its HIV infection rate.
Main article: HIV/AIDS in Asia
13.1.2
13.1.3
13.1.5 Americas
Caribbean
The HIV prevalence rate in South and South-East Asia Main article: HIV/AIDS in the Caribbean
is less than 0.35 percent, with total of 4.2 4.7 million adults and children infected. More AIDS deaths The Caribbean is the second-most aected region in the
13.1. BY REGION
world.[12] Among adults aged 1544, AIDS has become
the leading cause of death. The regions adult prevalence rate is 0.9%.[12] with national rates ranging up to
2.7%.[23] HIV transmission occurs largely through heterosexual intercourse, with two-thirds of AIDS cases in
this region attributed to this route. Sex between men is
also a signicant route of transmission, even though it is
heavily stigmatised and illegal in many areas. HIV transmission through injecting drug use remains rare, except
in Bermuda and Puerto Rico.
Central and South America
Main article: HIV/AIDS in Latin America
117
men today, including Michael Majeski, who believes
meth is the catalyst for at least 80% of seroconversions currently occurring across the United States, and
Tony Zimbardi, who calls methamphetamine the number
one cause of HIV transmission, and says that high rates
of new HIV infection are not being found among noncrystal users. In addition, various HIV and STD clinics across the United States report anecdotal evidence
that 75% of new HIV seroconversions they deal with
are methamphetamine-related; indeed, in Los Angeles,
methamphetamine is regarded as the main cause of HIV
seroconversion among gay men in their late thirties.[26]
The chemical methamphetamine, in and of itself, cannot infect someone with HIV.
Washington, D.C., the nations capital, also has the nations highest rate of infection, at 3%. This rate is comIn these regions of the American continent, only parable to what is seen in west Africa, and is considered
Guatemala and Honduras have national HIV prevalence a severe epidemic.[27]
of over 1%. In these countries, HIV-infected men outIn Canada, nearly 60,000 people were living with
number HIV-infected women by roughly 3:1.
HIV/AIDS in 2005.[28] The HIV-positive population continues to increase in Canada, with the greatest increases
amongst aboriginal Canadians.[29] As in Western Europe,
United States and Canada
the death rate from AIDS in North America fell sharply
with the introduction of combination AIDS therapies
Main articles: HIV/AIDS in the United States and
(HAART).
HIV/AIDS in Canada
In the United States, young African-American women are
also at high risk for HIV infection.[30] African AmeriThe adult prevalence rate in this region is 0.7% with
cans make up 10% of the population but about half of
over 1 million people currently infected with HIV. In the
the HIV/AIDS cases nationwide.[31] This is due in part
United States from 20012005, the highest transmission
to a lack of information about AIDS and a perception
risk behaviors were sex between men (4049% of new
that they are not vulnerable, as well as to limited access
cases) and high risk heterosexual sex (3235% of new
to health-care resources and a higher likelihood of sexcases).[24] Currently, rates of HIV infection in the US are
ual contact with at-risk male sexual partners.[32] There
highest in the eastern and southern regions, with the exare also geographic disparities in AIDS prevalence in
ception of California. Currently, 35,00040,000 new inthe United States, where it is most common in the large
fections occur in the USA every year. AIDS is one of
metropolitan areas of the East Coast and California and
the top three causes of death for African American men
in urban areas of the Deep South.[33] Rates are lower in
aged 2554 and for African American women aged 35
Utah, Texas, and Northern Florida.[33]
44 years in the United States of America. In the United
States, African Americans make up about 48% of the to- Since 1985, the incidence of HIV infection among
tal HIV-positive population and make up more than half women has been steadily increasing. It is currently esof new HIV cases, despite making up only 12% of the timated that at least 27% of new HIV infections are
population. The main route of transmission for women in women.[34] There has been increasing concern for
is through unprotected heterosexual sex. African Ameri- the concurrency of violence surrounding women infected
can women are 19 times more likely to contract HIV than with HIV. In 2012, a meta-analysis showed that the
rates of psychological trauma, including Intimate Partother women.[25]
ner Violence and PTSD in HIV positive women were
In the United States in particular, a new wave of infection
more than ve times and twice the national averages,
is being blamed on the use of methamphetamine, known
respectively.[35] In 2013, the White House commissioned
as crystal meth. Research presented at the 12th Annual
an Interagency Federal Working Group to address the inRetrovirus Conference in Boston in February 2005 contersection of violence and women infected with HIV.[36]
cluded that using crystal meth or cocaine is the biggest
single risk factor for becoming HIV+ among US gay men, A review of studies containing data regarding the
contributing 29% of the overall risk of becoming positive prevalence of HIV in transgender women found that
and 28% of the overall risk of being the receptive partner nearly 11.8% self-reported that they were infected with
HIV.[37] In the National Transgender Discrimination Surin anal sex.[26]
vey, 20.23% of black respondents reported being HIVIn addition, several renowned clinical psychologists now
positive, with an additional 10% reporting that they were
cite methamphetamine as the biggest problem facing gay
118
13.1.6
13.1.8 Oceania
13.1.7
Western Europe
13.4 Notes
[1] Cohen, MS; Hellmann, N; Levy, JA; DeCock, K; Lange,
J (April 2008). The spread, treatment, and prevention of HIV-1: evolution of a global pandemic.
The Journal of Clinical Investigation 118 (4): 1244
54. doi:10.1172/JCI34706. PMC 2276790. PMID
18382737. Retrieved 17 September 2012.
[2] Fact Sheet. UNAIDS.org. 2013. Retrieved 4 December
2013.
13.4. NOTES
119
120
References
Joint United Nations Programme on HIV/AIDS (UNAIDS) (2011). Global HIV/AIDS Response, Epidemic update and health sector progress towards universal access
(PDF). Joint United Nations Programme on HIV/AIDS.
Chapter 14
HIV/AIDS research
14.1 Transmission
See also: Circumcision and HIV
A body of scientic evidence has shown that men who are
circumcised are less likely to contract HIV than men who
are uncircumcized.[2] Research published in 2014, concludes that the sex hormones estrogen and progesterone
selectively impact HIV transmission.[3]
122
Only a vaccine is thought to be able to halt the pandemic. This is because a vaccine would cost less, thus
Main article: Management of HIV/AIDS
being aordable for developing countries, and would
not require daily treatment.[9] However, after over 20
research, HIV-1 remains a dicult target for a
Research to improve current treatments includes decreas- years of[9][10]
vaccine.
ing side eects of current drugs, further simplifying drug
regimens to improve adherence, and determining better In 2003 a clinical trial in Thailand tested an HIV vaccine
sequences of regimens to manage drug resistance. There called RV 144. In 2009, the researchers reported that
are variations in the health community in recommenda- this vaccine showed some ecacy in protecting recipients
tions on what treatment doctors should recommend for from HIV infection. Results of this trial give the rst suppeople with HIV. One question, for example, is deter- porting evidence of any vaccine being eective in lowermining when a doctor should recommend that a patient ing the risk of contracting HIV. Another possible vaccine
take antiretroviral drugs and what drugs a doctor may rec- comes from a novel gene therapy that alters the CCR5
ommend. This eld also includes the development of an- co-receptor permanently, preventing HIV from entering
cells.[11] Other vaccine trials continue worldwide.
tiretroviral drugs.
123
donors.[17][19]
124
[12] http://news.wustl.edu/news/Pages/25061.aspx
14.13 References
[1] Vijay Nema (2015-07-29). Current Trends in AIDS Research.
[2] CDC. Male Circumcision.
[3] Diana Goode, Meropi Aravantinou, Sebastian Jarl, Rosaline Truong, Nina Derby, Natalia Guerra-Perez, Jessica Kenney, James Blanchard, Agegnehu Gettie, Melissa
Robbiani, Elena Martinelli (May 15, 2014). Sex Hormones Selectively Impact the Endocervical Mucosal Microenvironment: Implications for HIV Transmission.
PLOS. doi:10.1371/journal.pone.0097767.
[4] Zhang C, Zhou S, Groppelli E, Pellegrino P, Williams I,
Borrow P, Chain BM, Jolly C (2015). Hybrid Spreading Mechanisms and T Cell Activation Shape the Dynamics of HIV-1 Infection. PLOS Computational Biology
11 (4): e1004179. doi:10.1371/journal.pcbi.1004179.
PMID 25837979.
[5] Perelson AS, Ribeiro RM (2013). Modeling the withinhost dynamics of HIV infection. BMC Biology 11 (1):
96. doi:10.1186/1741-7007-11-96.
[6] ScienceDaily (August 29, 2014). Surprising discovery:
HIV hides in gut, evading eradication.
[7] Strikingly early seeding of HIV viral reservoir shown in
study. ScienceDaily. July 20, 2014.
[8] Horvath S, Levine AJ. (2015). HIV-1 infection accelerates age according to the epigenetic clock.. J Infect Dis:
jiv277. PMID 25969563.
125
126
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Hne123, Maxhaase, Whyt74, Leafyplant, Silvercharcoal5, Hummer0800, Bonzo1980, Sterling32157, Robert s. walker, PDFbot, Optigan13, David Condrey, Nikkul, Merechriolus, Edref, Madhero88, Critizin, Alborz Fallah, Eubulides, Oxycotton, Geo Clapham, Lova
Falk, LoverOfKIds, Ball of pain, Falcon8765, Softlavender, Ronjohn, MCTales, Mallerd, Jeutz, Truthanado, Careet, Allyliker88, Doc
James, AlleborgoBot, Wisamzaqoot, Heliocybe, Tumadoireacht, EmxBot, CMBJ, Mew626, TalHurner, Thecat22, SieBot, R3cusant,
StAnselm, Toucansam554, Why-not-have-this-name, Themarkofstupid, St.Isaiah, YonaBot, Haugen-Dazs, Graham Beards, BotMultichill,
Ori, Hingram, Majesteit, Josconklin, Dawn Bard, Mwms8740, Ptkobj, Hugo Merck~enwiki, Srushe, Pain Griever, Shawnbarth, Flyer22
Reborn, Pizzalvr94, Memeccqouii, Gman160, Nopetro, ScottyFracture, Mimihitam, Gulgens watchtower, Bert79, Elisardojm, Sapovadia, Lightmouse, Timerrill, Macy, Retireduser1111, Kalleha, Habituallinestepper, Wickb55, Randomblue, Realm of Shadows, Mudkipsblah, Florentino oro, Troop350, Denisarona, Ghetto musick, Luvndance23, ImageRemovalBot, Jstevenharper, SallyForth123, Leranedo,
Sysoon, D cushman, Dollrocker, Twinsday, ClueBot, SummerWithMorons, Zeke8888, Brian Tjoe-Nij, Jereystringer, PipepBot, Djdetroit, Badger Drink, TableManners, Techdawg667, EoGuy, Wick3dd, Nnemo, Etherealwyrm, Ahoy1, Doseiai2, Ikarus14, Irish heckler,
Peter Grin yay, Bfuente1, Cam27, Baegis, Ledinlaind, Debangshu Mukherjee, Msamplin, Stylteralmaldo, Kr4d0n, LMLG1, Golem25,
MagyarFiatalember, Namazu-tron, Auntof6, Bbehan1993, Wutizevrybudylookingat?, Nipa123456789, DragonBot, Dwrcan, Zerotran0,
Resoru, Mastematt, Bde1982, Megamanx1367, KyuubiSeal, Poopmonkey222, MacedonianBoy, NuclearWarfare, Chefallen, Aurora2698,
Veggiehead, World, Jotterbot, Medos2, Riccardo Riccioni, Singhalawap, Jackrm, Redthoreau, Pstalker, BOTarate, Mlas, Bobbytheonlyone, Sarindam7, SDY, Dili85, Kiensvay, Darkicebot, Bola1235, Alden Loveshade, Leorawk, Mr. Gerbear, Falcor7, Matthew avent,
Moviefan13, Emmette Hernandez Coleman, Pichpich, Roxy the dog, Skoojal, Hotdong1, CaRzRlIfE, Yc183, Doddzy89, Rhyno007,
Sonyray, Zodon, Shoemakers Holiday, Owl order, Lguerrac, Bazj, Addbot, Tightjeans101, Krawndawg, Keeperofsoap, DOI bot, Mabdul, DougsTech, Convicious, Nestorius, Dualdraco, MartinezMD, Damiens.rf, Diptanshu.D, NjardarBot, JPLei, Sherri.a.anderson, Wildcursive, CarsracBot, Demonaire Rai, BepBot, Sussmanbern, AndersBot, Fottry55i6, FiriBot, Keepcalmandcarryon, LinkFA-Bot, Lownsclear, Numbo3-bot, Bguras puppy, ToonIsALoon, Jarble, Luckas-bot, Yobot, Granpu, Ptbotgourou, TaBOT-zerem, The Earwig,
Kilom691, VaderRacer, Oscar glutermerck, Bonne Nuit Bijou, Wurzel91, Bugnot, Kaaskop6666, KamikazeBot, AlexLevyOne, Raimundo
Pastor, AnomieBOT, AaRH, Awkwardwalker, Ibrowsally, Bluerasberry, Mann jess, Mahmudmasri, Danno uk, Citation bot, Er Cicero, Jamiemaloneyscoreg, GB fan, Analphabot, Cre-8, Xqbot, Zad68, Nxtid, Meewam, Parthasarathy B, Etherealstill, Gatorgirl7563,
Sir Stanley, Nasa-verve, GrouchoBot,
, Tomballguy, Scarletlathe, SassoBot, MemoZoe, Traord09, Alialiac, Smallman12q, Ukfswmart, FreeKnowledgeCreator, StoneProphet, FrescoBot, Skydeepblue, Tobby72, Krj373, JAdams1776, Nojan, D'ohBot, Kiwimankid,
Contentmaven, Timlovesaaron, Starsheditor, Citation bot 1, Galmicmi, AstaBOTh15, Cressmj, Stargnoc, FILWISE, Loyalist Cannons,
Jackrace, AmateurEditor, A8UDI, Bmclaughlin9, RedBot, Mikeylane, Shakunneed, Hyperduc, TobeBot, Trappist the monk, Lotje, Zakawer, Dinamik-bot, Inferior Olive, Don'tDrinkTheKoolAid, Gazpr, Connelly90, Diannaa, Hop12009, Tbhotch, Pierpao, RjwilmsiBot,
7mike5000, DexDor, HanAre, WildBot, Innitesimus, DASHBot, ToMMiTTo, Vinnyzz, EmausBot, ImprovingWiki, WikitanvirBot, Catgunhome, Dadaist6174, Distal24, Studiodan, GoingBatty, Dishcmds, Sepguilherme, AvicBot, ZroBot, John Mackenzie Burke, H3llBot,
Gniniv, Aaa1, AManWithNoPlan, Highvale, Ozweepay, Brandmeister, Dkevanko, Operative67, Steelpaw, Gnhxwarri0r3, Wipsenade,
Ego White Tray, J341933, MichaelKovich, Ilostmybrain, Chibps, Spatulli, Maximilianklein, Homunculus7, FeatherPluma, Amlui89,
Mjbmrbot, ClueBot NG, Shellyquade, OnlyEvolutions, Deth2ShawtyYo, Jacksoncw, Jdsousa1, Gwendal, Cardnl12, Jdcollins13, Hindustanilanguage, FlorentineD, Hazhk, Braincricket, CaroleHenson, GlassLadyBug, Helpful Pixie Bot, Dirk Hudson, TotalFailure, Tholme,
Daviddwd, Bibcode Bot, Samuelredick, BG19bot, Jakub199501, Mleoking, AvocatoBot, Cold Season, Gautehuus, Mark Arsten, SamZR,
Sturmavik, Cadiomals, Soerfm, M713c041, NaciViviMori, Harizotoh9, NotWith, Bsungp1993, Zedshort, Caypartisbot, Alcohology, WikiHogan654, Jonadin93, BattyBot, Biosthmors, Teammm, Randy102, Ligne11, Sermadison, DiseaseAction5844, Aliwal2012, Banking
honesty, Khazar2, TylerDurden8823, Soulparadox, SuperHero2111, Matt.haraszkiewicz, JYBot, Dexbot, Rezonansowy, Yash!, Mogism,
Magicturnips, Tessmac9708, Mahan, AndreaLange, Hobawido, ComfyKem, Misomucho, Reatlas, FairHousing, SimplesC, Epicgenius,
Alan, WikiU2013, Newthoughts34, AmericanLemming, Austinpk, Cgayhea, TheRobot Vegetable, Everymorning, Naruto9181, CensoredScribe, Clr324, HoboMcJoe, Pgcudahy, Jackmcbarn, Chemistry74, Rishabh2211, Aarongaming100, Coreyemotela, Anrnusna, 22merlin,
Savvyjack23, Monkbot, ShawntheGod, Suzi at NAT, Vittunaama, Qwertyxp2000, GoldenGuy23, AndyRatchick, Jack Matelot, Soupvector, Lise-lyse, MoreTomorrow, Emily Temple-Wood (NIOSH), Gamingforfun365, KasparBot, Park Lexington, ShartedOnU, Matterington
and Anonymous: 1463
Pathophysiology of HIV/AIDS Source: https://en.wikipedia.org/wiki/Pathophysiology_of_HIV/AIDS?oldid=672411068 Contributors:
Bearcat, Malcolma, Doc James, Yobot, FrescoBot, Brandmeister, Sermadison, Monkbot and Anonymous: 3
Diagnosis of HIV/AIDS Source: https://en.wikipedia.org/wiki/Diagnosis_of_HIV/AIDS?oldid=685994960 Contributors: AxelBoldt, The
Anome, ChangChienFu, Modemac, Karada, Gbleem, Minesweeper, Kosebamse, Ronz, Nikai, Cratbro, Zoicon5, Wilke, Frazzydee, SD6Agent, Josh Cherry, Donreed, Nunh-huh, Jfdwol, Chowbok, Beland, Adashiel, Ta bu shi da yu, Random contributor, Rich Farmbrough, FT2, Wk muriithi, Bender235, JoeSmack, Ttguy, MBisanz, Nonpareility, EurekaLott, Bobo192, Wood Thrush, Davidruben, Arcadian, Docvalium, Orangemarlin, Pion, Ombudsman, TenOfAllTrades, Uncle G, Tabletop, Clemmy, Sci guy, Rjwilmsi, Koavf, Ligulem,
Keimzelle, Pfctdayelise, Alphachimp, Vidkun, YurikBot, Peter G Werner, Epolk, Donwarnersaklad, Rodasmith, Gaius Cornelius, Eleassar, Geo NoNick, Tribune, Gadget850, Bilz0r, Bsheppard, 2over0, Patiwat, SaulPerdomo, TechBear, SmackBot, Ingenium, Nickst,
Trezatium, Edgar181, Betacommand, Chimeira, G716, Drphilharmonic, DMacks, DO11.10, Aroundthewayboy, Ryulong, Mdanh2002,
Jetman, Rigurat, Filipe.ribeiro, Fsiyavud, Macetw, CmdrObot, Chmee2, Keithh, DrunkenSmurf, Anthonyhcole, YechezkelZilber, Hopping, Robbieisfun, Timerrington, Lindsay658, Thijs!bot, Bobblehead, Leon7, Danielfolsom, .anacondabot, Acroterion, AIDSvideos, Magioladitis, MastCell, JNW, JamesBWatson, WhatamIdoing, Adrian J. Hunter, Yobol, J.delanoy, Guijarrosoy, Mikael Hggstrm, TottyBot, Paris75000~enwiki, Bonadea, Varnent, CardinalDan, Rquattrocchi, DocNartman, Una Smith, Optigan13, Luminum, Goozee,
Twooars, Doc James, Biscuittin, Mangostar, Stensun, DGGenuine, Mimihitam, Saphon, ClueBot, Icarusgeek, Pairadox, Mild Bill Hiccup, Uncle Milty, Doseiai2, Msamplin, John Nevard, Mumia-w-18, Besafe99, Bjorn I. Clever, Nocowardsoulismine, NJGW, DumZiBoT, Rapidscreenings, XLinkBot, NonvocalScream, Addbot, Shayer, Jacopo Werther, DOI bot, Older and ... well older, MartinezMD,
Abiather0712, Betty2006, MrAnderson7, Keepcalmandcarryon, RetroS1mone, Verbal, Lightbot, Electrosaurus, Luckas-bot, Yobot, Carbona, Ptbotgourou, Julia W, Backslash Forwardslash, AnomieBOT, Rubinbot, IRP, AmKaf, Arilo~enwiki, Citation bot, Aestasis, Daekl,
Scientopsy, Xqbot, Chrislipthorpe, Omnipaedista, LAlexanderson, Citation bot 1, Loyalist Cannons, RedBot, Mikeylane, Rdicker13,
NortyNort, HelenOnline, Kiaora74, Reach Out to the Truth, BK Wagner, ImprovingWiki, NJWriterM, Sindu5673, RA0808, HealthGal,
Daniel.r.furtado, Ayoungmm, Wikignome0530, ArtieFox, Martin Waldhausen, Gsarwa, Raviraiya, Janicejsantos, ClueBot NG, Akul5,
User441129, CaroleHenson, Yahahooey02, Helpful Pixie Bot, Idahoan57, Neptunes Trident, PTJoshua, Dipankan001, Michaelturken,
Biosthmors, Mavi17, SkepticalRaptor, Cyberbot II, Quixote11, ChrisGualtieri, MedMira, Dexbot, EyeTruth, EJM86, FieldsTom, Arripay,
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Images
File:AIDS_Clinic,_McLeod_Ganj,_2010.jpg Source:
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File:AIDS_Poster_If_You're_Dabbling_in_Drugs_1989.jpg Source: https://upload.wikimedia.org/wikipedia/commons/b/bd/AIDS_
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Source site: http://www.nlm.nih.gov/exhibition/visualculture/hivaids14.html Original artist: The original uploader was Grcampbell at
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File:AIDS_and_HIV_prevalence.svg Source: https://upload.wikimedia.org/wikipedia/commons/e/ee/AIDS_and_HIV_prevalence.svg
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prevalence_in_2002.png License: CC-BY-SA-3.0 Contributors: Based on Osmanov S, Pattou C, Walker N, Schwardlander B, Esparza
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PNG License: Public domain Contributors:
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being_administered.jpg License: CC BY-SA 3.0 Contributors: File made available by Equality Michigan through the LGBT Free Media
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