BIOL 584-Medical Microbiology

HIV-1 and HCV

Retrovirus (retroviridae)

AIDS, a sad story

Prevalence of AIDS (2008) in the US

The impact of the AIDS pandemic

AIDS pandemic - 2010

Progression towards AIDS

primary
infection

acute HIV syndrome

virus dissemination
seeding of lymphoid organs

death

opportunistic diseases
clinical latency

constitutional symptoms

onset of AIDS

Diseases associated with AIDS

Pathogen or Disease

Disease Description

Natural history of untreated HIV infection

The source of AIDS

HIV-1

chimpanzees

HIV-2

sooty mangabeys

Homo sapiens

Retroviridae
100nm
icosahedral or conical capsid

7-11kb, linear ss(+)RNA

two copies of genome
reverse transcriptase

lenti: slow
HIV-1

Baltimores viral classification

I: dsDNA
II: ssDNA
III: dsRNA
IV: (+)ssRNA
V: (-)ssRNA
VI: ssRNA-RT viruses
VII: dsDNA-RT viruses

HIV virus

Group:

Group VI (ssRNA-RT)

Family:

Retroviridae

Genus:

Lentivirus

Species:

Human immunodeficiency virus 1

Human immunodeficiency virus 2

The central dogma

DNA

RNA

Protein

Retroviridae
RNA

DNA

RNA

Protein

Genome of HIV
HIV-1 / SIVcpz
y

vif

gag
pol

p24

p6

p7

vpu
vpr
vpr

env
nef

rev
tat

p17
gp120

capsid nucleocapsid matrix

PR

RT

IN

protease reverse RNase H integrase

transcriptase

gp41

exposed transmembrane
envelope
envelope

HIV live cycle

binding and fusion

maturation
budding

entry
reverse transcription

assembly
processing
nuclear import

early stages

translation

late stages

RNA export

transcription

integration

HIV live cycle

T-cell

Adapted from Tibotec

HIV reverse transcription

pol

RNAaseH

1st strand transfer

pol, RNaseH
tRNA:
viral genomic RNA:
"minus" strand DNA:
plus" strand DNA:

pol

RNaseH

pol

2nd strand transfer

HIV diversity: The many clades of HIV-1

Tropism of HIV
T-tropic HIV isolate

M-tropic HIV isolate

inhibition of entry by the natural ligands of CCR5 and CXCR4 chemokine coreceptors

Entry and Exit

binding

fusion

nucleocapsid adapts the

envelope during budding

budding

immature

mature

HIV infectivity

Nef

1.
2.
3.

Interference with cell signaling pathways

CD4 downregulation
Enhancement of viral infectivity
D. Wolf and A Baur

Vif

Vif interacts with the cytidine deaminase APOBEC3G,

preventing its incorporation in newly formed viruses

HIV and the immune system

latent infection

active infection

Adapted from

HIV immune escape

basic immunology takes place

immune escape

high mutation rates of HIV allows the virus to escape adaptive immune response

HIV-mediated disease
CD4+ T cells especially susceptible

DC
(through DC-sign)

migration of HIV bearing activated DCs

to helper T cells in lymph nodes

T cell

infection of helper T cells specific for HIV peptides

virus replication

reduction in HIV specific helper T cell number

decreased activation and survival of cytotoxic CD8+ T cells

decreased ability to destroy infected cells

loss of memory helper T cells, and inability to

replace them leads to increasing immunodeficiency

Adapted from
Nature Medicine
9, 839 (2003)

CD4+ T cells depletion

CD4 and CCR5 expression is highest in memory T cells (residing in mucosal effector lymphoid tissue,
major site of mucosal immunity )
HIV rapidly infects and destroys these cells, even in patients undergoing therapy
progression to AIDS probably depends on how well cells destroyed by the virus are replaced
our immune reaction further activates HIV replication

Symptoms

The perfect vaccine

Merck rAd5-Gag/Pol/Nef vaccine

a: Optimal vaccine
b: Sub-optimal vaccine

Adapted from: Dan H. Barouch

Nature 455, 613-619(2 October 2008)

So, please, safe sex

HIV, from start to end

HIV binding to lymphocyte

HIV budding from lymphocyte

Flavivirus (Flaviviridae)

Flaviviridae
icosahedral 40-60nm
9-12kb (+) ssRNA, monopartite
enveloped
West Nile virus
Hepatitis C virus

Baltimores viral classification

I: dsDNA
II: ssDNA
III: dsRNA
IV: (+)ssRNA
V: (-)ssRNA
VI: ssRNA-RT viruses
VII: dsDNA-RT viruses

Yellow fever virus

Flaviviridae genera
genus

members (examples)

Flavivirus

yellow fever virus

dengue fever virus
Japanese encephalitis virus (such as WNV)

Pestivirus

bovine virus diarrhea

Hepacivirus

Hepatitis C virus

Group

Group IV ((+)ssRNA)

Group VII (dsDNA-RT)

Group IV ((+)ssRNA)

Family

Picornaviridae

Hepadnaviridae

Flaviviridae

Genus

Hepatovirus

Orthohepadnavirus

Hepacivirus

Species

Hepatitis A virus

Hepatitis B virus

Hepatitis C virus

genome structure
Flavivirus
Pestivirus
Hepacivirus

IRES

-AAAAAA

HCV pathogenesis

200 million infected with HCV worldwide

4 million Americans infected with HCV
~10,000 American deaths from HCV-related disease

blood-to blood transmission

HCC, a liver tumor that is the third leading cause of cancer death

mutation in epidermal growth factor (EGF) to blame?

core protein and p53?
immune escape

HCV and HCC

HCV infection
(30% icteric)
80%

High bilirubin in blood

(jaundice, icteric)

chronic hepatitis
30-50%
(after 10-30yrs)

Cirrhosis
IFNa
2-6% per yr

hepatocellular carcinoma

HCV IRES
IRES

internal ribosome entry site

5
3

Hepatitis C virus genome

the RNA genome is a perfect mRNA
translated into a single polyprotein
processed by proteases

Adapted from Mol Virol Univ of Heidelberg

Hepatitis C virus proteins

Core (C)
E1, E2

RNA binding protein forming the nucleocapsid

transmembrane proteins that heterodimerize, embedded into the lipid viral envelope

most of the NS proteins NS2 - NS5B are required for multiplication of the viral RNA
P7

small hydrophobic peptide possibly a virioporin

NS2/N-NS3
NS3/4A

NS2/3 autoproteinase responsible for cleavage at the NS2/3 junction

bifunctional protein for polyprotein processing and RNA replication (helicase)

NS4B

membrane protein for formation of membranous web (for RNA replication?)

NS5A

membrane-anchored protein (for viral replication?)

NS5B

RNA-dependent RNA polymerase

HCV life cycle

Production of infectious hepatitis C virus particles in cell culture

Adapted from Mol Virol Univ of Heidelberg

END

HIV infectivity
Vpu

inhibition of NF-kB blocks anti-apoptotic

proteins synthesis such as the Bcl-2
family proteins or TNFR complex proteins
Vpu-induced degradation of CD4

Vpu-induced apoptosis

HIV and cell cycle arrest

Polo like kinase-1

direct
indirect
Mitosis Promoting Factor

MPF cannot be activated

Vpr induces a G2/M cell cycle arrest and eventually apoptosis

Retrovirology 2007 4:27