The role of immune responses in

HIV-1 Infection

Marylyn M. Addo, MD/PhD

Partners AIDS Research Center
Massachusetts General Hospital
Harvard Medical School
Boston, MA USA
 Altfeld_CAP150_03

Natural History of HIV-1

1000 symptoms
HIV RNA copies/ml

106
CD4
800
CD4 per mm3

105
600 HIV RNA VZV
104
TB
400
Kaposi Sarcoma

200
PCP
CMV MAC Crypto Lymphoma

1 5 10 15
Time (years)
 The level of HIV in the blood stream
predicts subsequent survival
RNA particles/ml plasma

Rapid Progression

Viral set point

Slow Progression

One year
What influences viral load in HIV
infection?
Viruses are not able to
reproduce on their own
 New virus
assembly

2-3 Days
 Viral set point is
determined
by number of viruses
produced by infected cells
 Potential factors
influencing the viral set
Attenuated point
virus

Host immune
response

Host genetic
factors
 Potential factors
influencing the viral set
Attenuated point
virus

Host immune
response

Host genetic
factors HAART
 Example: Sidney blood bank cohort
Virus had a “mistake” in the nef gene
Attenuated
viruses

New virus
assembly

2-3 Days
 Host genetic
Attenuated factors
viruses
 Co-receptor polymorphisms
can prevent entry of virus into cells
32 base pair deletion
in CCR5

CD4 CCR5
Some molecules on the cell of an individual are associated
with improved viral control and slow disease progression

B27 B57

Migueles, PNAS 97:2709, 2000

 Host genetic
Attenuated factors
viruses

Host immune
responses
Humoral Immune System: Neutralizing Antibodies

New virus
assembly

B cell
Cellular immune
system: Soluble
Killer T cells factors
Cytotoxic T cell CTL

New virus
assembly
 Th Soluble
factors

CTL

New virus
assembly

B cell

Th
 Th

B cell

CTL

Th
 The Generals
(T helper cells trained to target HIV)
 Enemy
Infantry
Infected cell
(CTL)
Generals
(T Helper cells)
Why are the generals absent in
most infected persons?
 Enemy
Infantry
Infected cell
(CTL)
Generals
(T Helper cells)
 Virus-Specific T Helper Cells:
Essential for Maintenance of Effective CTL
Relative magnitude

Viremia
CTL

Viremia
CTL

Th cells absent Th cells present

Is there any way to enhance the
immune response against HIV?
 Infantry Enemy
(CTL) (Infected cells)
Generals
(T helper cells)
 Infantry Enemy
(CTL) (Infected cell)
Generals
(T Helper cells)

HAART
 Effect of Early Treatment
on the Generals
(HIV-Specific T Helper Cells)
Magnitude of Helper Cells

1000

100

10

1
0 20 40 60 80

Weeks on Treatment
What happens if you stop
treatment?
 Early treatment of acute HIV infection
followed by treatment interruption
viral load (copies RNA/mL)

HAART

160000
120000
80000
40000
0
0 5 10 15 20 25 30 35 40

Weeks after first treatment interruption

 Very early treatment with HAART
leads to enhanced natural control
of HIV
 Where else do we find evidence for
immune control in AIDS virus infection ?
■ In monkey studies, removing killer cells led to
dramatic increases in viral load and restoring
Killer T cells in those same monkey studies led to
suppression of viral load
■ Individuals with high levels of Killer T cells have
been shown to have low viral loads
■ Two interesting groups of individuals
— HIV-1 long-term nonprogressors (LTNP)
— HIV-1 exposed, but uninfected individuals (HEPS)
 LTNP
• Infected 21 years
• Normal T cells
• Undetectable viral load
• Never on anti-HIV meds

LTNP have strong and

broadly directed killer cell
responses and helper cell
responses
HEPS
■ Most well known:
— Nairobi sex worker cohort
(Rowland-Jones et al.)
— Found killer T cell
responses in these HEPS,
that may contribute to
protection from HIV
— Our group: collaboration
with Lusaka, Zambia (PI:
Susan Allen) studying killer
cells in discordant couples
and their partners
Poster session
Thursday 12-2 pm (Addo)
 Vaccine development
■ Based on these pieces of data, it is felt that an
effective HIV-1 vaccine needs to elicit cellular
immune responses, in particular Killer T cell
responses +/- Helper T cell responses
■ Most recent and compelling data derive from
monkey studies demonstrating that Killer T
cell have an impact on vaccine efficacy in this
setting (Robbinson, Barouch/Letvin, Shiver)
■ Many vaccine approaches/trials currently in
study
 Our current Research

■ Understanding of total the killer T cell and

helper cell response against HIV, not only
to single proteins like previous studies.
■ Analysis of the virus by sequencing
Bruce Walker morning Tuesday plenary
Addo A05 Tuesday 14-15:30
More research needed for other
virus types and other ethnicities
■ Durban, RSA
■ Immune responses in Clade
C-Infection
■ Mother to child transmission
and pediatric treatment and
treatment interruption
studies
■ NIH contract Epitope
mapping in Non-Caucasians
 Lab

Nelson Mandela School of Medicine

University of Natal
Why is HIV not controlled by
the immune system like
other chronic viral
infections?
Mono

Chicken pox

Herpes simplex
 Problems

■ VIRAL ESCAPE

■ VIRAL DIVERSITY
How HIV mutates to escape
Killer T-cells
 Viral escape

Examples:
■ Goulder et al, Nature 2001

— Viral escape mutants can be transmitted

from mother to child
■ Barouch et al, Nature 2002
— Loss of viral control in a vaccinated animal
associated with viral escape in one epitope
 Viral Diversity
Comparing Viruses:
How much does HIV evolve compared
to Flu?

Less Variation More Variation

1997-1998 1996
Canadian Flu Global Flu

Influenza variation
compared to HIV variation
1997-1998 1996
Canadian Flu Global Flu

Influenza variation
compared to HIV variation
1990-1991 1997
Amsterdam Dem Rep of Congo
 The extreme variability of HIV
over time is a major impediment
to immune control, effective drug
therapy and vaccine development
 Acknowledgements
■ Marcus Altfeld
■ Xu Yu
■ Almas Rathod
■ Cecily Fitzpatrick
■ Paul Lee
■ Philip Goulder
■ Christian Brander
■ Eric Rosenberg Funding Sources:
■ Bruce Walker German Research Council (DFG)
amfAR
Concerned Parents for AIDS Research (CPFA)
HLA-B27 is associated with slow progression to AIDS

106

105
Viral
104
Load
3
n = 10 HLA-B27+
10

102
The dominant CTL response in HLA-B27+ individuals:
HIV Gag p24 KK10 epitope

K I L
W I G L

R L
K

HLA B27 molecule

B27-KK10 escape is associated with elevated viral load

6 All Arg/Lys
10
at P2
105
Viral
104
Load
103
p=0.025
102
Controllers Non-controllers
 HIV Gag p24 KK10 epitope

K
K M
I L
W I G L

R L K

HLA B27 molecule

B27-KK10 is recognized more frequently
in adult than in pediatric HIV infection

100% n=21 86%

1.55% pbmc 80% p=0.02
2.73% CD8s
60%
CD8

40% n=6 33%

20%
0%
IFN-γ
Adult Pediatric
 B27-KK10 is not recognized in
children of B27-positive mothers

1925
2000

1600
IFN-γ
SFC/ 1200

million 800
PBMC
400
0 0 0
0

043-C 002-C 048-C 049-C

B27-ve mother B27+ve mothers
B27-KK10 non-recognition associated with P2 anchor mutation

No P2 anchor
mutation
2000

1600 P2 anchor
IFN-γ
SFC/ 1200 mutation
million shared with
800
PBMC mother
400
0 0 0
0

043-C 002-C 048-C 049-C

B27-ve mother B27+ve mothers