Download Why was HIV-1 able to cause the AIDS pandemic?

Why was HIV-1 able to cause
the AIDS pandemic?
Garland Science, 2005
Frank Kirchhoff
Institute of Molecular Virology
Ulm University Medical Clinic
HIV: structure and genome
10 genes and 10.000 basepairs (humans ~21.000 and 3 billion)
HIV: structure and genome
10 genes and 10.000 basepairs (humans ~21.000 and 3 billion)
HIV: structure and genome
10 genes and 10.000 basepairs (humans ~21.000 and 3 billion)
HIV: why is the virus so successful?
• Camouflage
• Highly variable
Strong Glycosylation, conserved domains
are „masked“ and only transiently exposed
Envelope trimer
• Can become invisible
• Hide
• Immunodeficiency
• Cell-Cell Spread
• Immune response is too slow
• Viral Antagonists
• Manipulation of host cells
Pancera et al., Nature (2014)
HIV: why is the virus so successful?
• Camouflage
• Highly variable
• Can become invisible
• Hide
• Immunodeficiency
• Cell-Cell Spread
• Immune response is too slow
• Viral Antagonists
• Manipulation of host cells
Error rate of RT ~ 1 : 10.000
Generation time 1-2 days
Billions of progeny virions
HIV: why is the virus so successful?
• Camouflage
• Highly variable
• Can become invisible
• Hide
• Immunodeficiency
• Cell-Cell Spread
• Immune response is too slow
• Viral Antagonists
• Manipulation of host cells
Error rate of RT ~ 1 : 10.000
Generation time 1-2 days
Billions of progeny virions
HIV: why is the virus so successful?
• Camouflage
Latent infection of long-living cells
• Highly variable
• Can become invisible
• Hide
• Immunodeficiency
• Cell-Cell Spread
• Immune response is too slow
• Viral Antagonists
• Manipulation of host cells
Stevenson, Nat. Med. 2003
HIV: why is the virus so successful?
• Camouflage
Infection of specific
body compartments
• Highly variable
• Can become invisible
• Hide
• Immunodeficiency
• Cell-Cell Spread
• Immune response is too slow
• Viral Antagonists
• Manipulation of host cells
McArthur et al. Ann Neurol. (2010)
HIV: why is the virus so successful?
• Camouflage
• Highly variable
• Can become invisible
• Hide
• Immunodeficiency
• Cell-Cell Spread
• Immune response is too slow
• Viral Antagonists
• Manipulation of host cells
HIV destroys CD4+ helper T-cells
HIV: why is the virus so successful?
• Camouflage
Direct transfer: Protection against CTLs & Abs
• Highly variable
• Can become invisible
• Hide
• Immunodeficiency
• Cell-Cell Spread
• Immune response is too slow
• Viral Antagonists
• Manipulation of host cells
Haller & Fackler, Biol. Chem. (2008)
HIV: why is the virus so successful?
• Camouflage
Cytotoxic T cells come too late
(antibodies anyway…)
• Highly variable
• Can become invisible
• Hide
• Immunodeficiency
• Cell-Cell Spread
• Immune response is too slow
• Viral Antagonists
• Manipulation of host cells
Haase, Nature (2010)
HIV: why is the virus so successful?
• Camouflage
• Highly variable
• Can become invisible
• Hide
• Immunodeficiency
• Cell-Cell Spread
• Immune response is too slow
•Viral Antagonists
• Manipulation of host cells
HIV-1: replication cycle
Restriction factors: cellular inhibitors of viral replication
TRIM5:
destabilization
of the viral capsid
APOBEC3G:
Hyper-Mutationen
Tetherin:
Hemmung der
Virusfreisetzung
Restriction factors: cellular inhibitors of viral replication
TRIM5:
destabilization
of the viral capsid
APOBEC3G:
hyper-mutations
Tetherin:
Hemmung der
Virusfreisetzung
Restriction factors: cellular inhibitors of viral replication
TRIM5:
destabilization
of the viral capsid
APOBEC3G:
hyper-mutations
Tetherin:
inhibition of
virus release
Humans developed a „natural combination therapy“
TRIM5:
destabilization
of the viral capsid
APOBEC3G:
hyper-mutations
Tetherin:
inhibition of
virus release
The number of restriction factors is increasing
TRIM5, APOBEC3G, tetherin, SamHD1, …
SerinC5
HIV-1 infection
control
SerinC5
Pizzato et al.
Nature, in press
Göttlinger et al.
Nature, in press
Restriction factors share some characteristics
1. inducible by interferons
2. interacting with viral components
3. under high positive selection pressure
GBP5: affects HIV-1 Env function
Restriction factors share some characteristics
1. inducible by interferons
2. interacting with viral components
3. under high positive selection pressure
GBP5: affects HIV-1 Env function
Key role in macrophages
http://interactive-biology.com
If there are so many anti-HIV factors:
Why do they NOT efficiently control HIV-1?
HIV-1: evasion or counteraction of antiviral factors
TRIM5:
destabilization
of the viral capsid
resistance
APOBEC3G:
hyper-mutations
Tetherin:
inhibition of
virus release
HIV-1: evasion or counteraction of antiviral factors
TRIM5:
destabilization
of the viral capsid
resistance
APOBEC3G:
hyper-mutations
Antagonist: Vif
Tetherin:
inhibition of
virus release
HIV-1: evasion or counteraction of antiviral factors
TRIM5:
destabilization
of the viral capsid
resistance
APOBEC3G:
hyper-mutations
Antagonist: Vif
Tetherin:
inhibition of
virus release
Antagonist: Vpu
Nef antagonizes SerinC5
nef-defective
Wild-type
control
control
SerinC5
SerinC5
Removal from
the cell surface
control
Nef
Pizzato et al., Nature, in press
HIV-1 evolved tools to antagonize restriction factors
HIV: why is the virus so successful?
Vif, Vpu, Vpr & Nef allow the virus to antagonize antiviral factors
Kirchhoff,
Cell Host & Microbe (2010)
If restriction factors are inactive against HIV-1:
are they good for anything?
Evolutionary arms race
or “red queen” hypothesis
Antiviral protein
Viral target
Host adapts
Resistance
Host adapts
Resistance
Now, here, you see, it takes all the running you can
do, to keep in the same place (Carroll, Lewis, 1998)
Antiviral proteins are highly variable and often species-specific
Monkey TRIM5 protects cats against FIV
FIV resistent
(Wongsrikeao et al.,
Nat. Methods 2011)
HIV: origin
~1920
HIV: spread
The AIDS pandemic
North America
980 000
Caribbean
440 000
Latin America
1.5 million
• 35 million people living with HIV
• 2.3 million infections per year
• about 35 million deaths
Western Europe
570 000
Eastern Europe
& Central Asia
1.2 million
East Asia & Pacific
North Africa
& Middle East
550 000
1.2 million
South
& South-East Asia
6 million
Sub-Saharan
Africa
29.4 million
Australia
& New
Zealand
15 000
UNAIDS/WHO 2013
HIV: original hosts - chimpanzees, gorillas & mangabeys
Bieniasz & Ho
Cell 2008
Some naturally infected monkeys do NOT develop disease
HIV/AIDS: origin
HIV-1 group N
HIV-1 group M
Kinshasa: 1959
HIV-1 group O
HIV-1 group P
HIV: field studies
Photos: courtesy of
Beatrice Hahn
Photos: courtesy of
Beatrice Hahn
HIV-1: multiple cross-species transmissions
Monkeys
Greater apes
Humans
Sauter et al., Cell 2010
HIV-1: multiple cross-species transmissions
barriers:
APOBEC3G, TRIM5, tetherin,…
APOBEC3G, TRIM5, tetherin,…
Sauter et al., Cell 2010
Recombination helped SIVs to cross the barrier
from monkeys to chimpanzees
recombination
Generation of a functional Vif
Adaptation to apes „inactivated“ human
TRIM5 and APOBEC3G
X
X
APOBEC3G, TRIM5, Tetherin
70 million
17
100.000
2
Courtesy Paul Spearman
Adaptation to apes „inactivated“ human
TRIM5 and APOBEC3G
Why did only HIV-1 group M
cause a pandemic?
70 million
17
100.000
2
Courtesy Paul Spearman
Tetherin: a broad-based inhibitor of virus release
SIV
MLV
HIV
HHV-8
Lassa virus
XMRV
Sauter and Kirchhoff, Curr HIV Res. 2011
Marburg virus
VSV
JSRV
PERV
Ebola virus
adapted from Murphy, UC, USA
Vpu antagonizes tetherin, which blocks virus release
and induces CD4 degradation
Neil et al., Nature 2008; Van Damme et al., Cell HMi 2008
Arias et al., 2011,
Frontiers in
Microbiology
Courtesy Paul Spearman
Tetherin is a barrier to successful zoonotic transmission
(Sauter et al., Cell HM 2009, Cell 2010; Retrovirology 2011; PLOS Path. 2012, others)
HIV-1 Vpu function
M
N
O
P
Tetherin
+
(+)
-
-
CD4
+
-
+
+
Sauter et al.,
Cell (2010)
Only HIV-1 M Vpu is “optimally” adapted to humans
Effective tetherin antagonism may promote HIV-1
transmission by enhancing genital shedding of virions
Effective tetherin antagonist
No tetherin antagonist
Bieniasz, CROI 2014
Most primate lentiviruses use Nef to antagonize tetherin
Jia et al., 2009; Sauter et al., 2009; Zhang et al., 2009
SIVcpz & SIV gor
Tetherin
Nef
CT
Perez-Caballero et al., 2009
Human tetherin contains a deletion that renders it resistent to Nef
Ancient origin of the protective deletion in human tetherin
(Sauter et al., Hum. Mut. 2011)
Neanderthal
Denisova
modern human
1.0
0.5
0.0 mya
VERY ancient origin of tetherin and its antiviral activity
~350 million years old
nhm.ac.uk
tybeemarinescience.org
HIV-1 group M switched from Nef to Vpu
Sauter et al., Cell HM 2009
SIVcpz & SIV gor
HIV-1 M & N
Tetherin
Tetherin
TM
Nef
CT
Vpu
HIV-1 group N is still adapting to humans
(Sauter et al., PLOS Path. 2012)
The most recently transmitted HIV-1 N strain
is fully active against human tetherin
HIV-1 O restored anti-tetherin activity of Nef in humans
(Kluge, Mack et al., Cell Host & Microbe 2014)
Why did only HIV-1 group M cause the AIDS pandemic?
It evolved Vpu as highly effective tetherin antagonist
Why does HIV-1 cause chronic immune activation and AIDS?
Differences between HIV-1 and SIVsmm or SIVagm:
Presence of vpu and differences in Nef function
Differences between HIV-1 and SIVsmm or SIVagm:
Presence of vpu and differences in Nef function
Nef is critical for efficient viral replication in vivo
(Kestler et al., Cell 1991; Deacon et al., Science 1995; Kirchhoff et al., New Engl J Med. 1995)
nef+: sAIDS
nef: No disease
Nef: structure and function
Nef: structure and function
CD4
cell membrane
myristoylated
globular core
Uptake
Nef
AP2
cellular
receptors
2 flexible
loops
endosome
AP
Uptake into
the cell
and degradation
degradation
lysosome
Nef is expressed early and at very high levels
Nef: the “swiss army knife” of the virus
Kirchhoff
Cell Host & Microbe 2010
Vpu facilitated changes in Nef function
(Schindler et al., Cell 2006; Schmoekel et al., JVI 2011)
HIV-1: AIDS
Some SIVs: No disease
Inflammation
Apoptosis
HIV-1, SIVcpz
Most SIVs
HIV-2
HIV-1 and its
Vpu containing
SIV precursors
Most primate
lentiviruses
Vpu facilitated changes in Nef function
(Schindler et al., Cell 2006; Schmoekel et al., JVI 2011)
Nef unable to
downmodulate
TCR-CD3
HIV-1, SIVcpz
Most SIVs
HIV-2
HIV-1 and its
Vpu containing
SIV precursors
Most primate
lentiviruses
Vpu facilitated changes in Nef function
(Schindler et al., Cell 2006; Schmoekel et al., JVI 2011)
Nef downmodulates
TCR-CD3
HIV-1, SIVcpz
Most SIVs
HIV-2
HIV-1 and its
Vpu containing
SIV precursors
Most primate
lentiviruses
Most primate lentiviruses suppress T cell activation
whereas HIV-1 just deregulates it
(Schindler et al., Cell 2006; Arhel et al., JCI 2008; Khalid et al., JVI 2012)
Inefficient down-modulation of TCR-CD3 by Nef
correlates with low numbers of CD4+ T cells
(Schindler et al., PLOS Path., 2008; Khalid et al., JVI 2012)
SIVsmm infected
Sooty mangabeys
Viremic HIV-2 infected
Human individuals
Rare „HIV-1-like“ SIVsmm strains cause
severe CD4+ T cell loss but NO disease
Milush et al., J. Immunol. 2007; Schmökel et al., Cell Reports 2014)
Envelope
CCR5
CXCR4
Loss of Nef-mediated
CD3 downmodulation
CD4-negative helper T cells and low levels of immune activation
Loss of the protective CD3 downmodulation function of Nef
occurred specifically in vpu containing viruses
vpu
Kirchhoff, Nat. Rev. Microbiology 2010
What is the link between Vpu and Nef function?
vpu
Kirchhoff, Nat. Rev. Microbiology 2010
Link: inhibition of NF-κB-mediated antiviral gene expression
Stimulation
antiviral gene expression
Down-modulation of TCR-CD3 by Nef blocks T-cell activation
(Schindler et al., Cell 2006, others)
HIV-2, most SIVs
Nef
X
„Resting“ phenotype
Vpu inhibits NF-κB-mediated antiviral gene expression
(Sauter et al., Cell Reports 2015)
HIV-1 and its precursors
HIV-2, most SIVs
Nef
X
Vpu
X
„Resting“ phenotype
Apoptosis, inflammation
Vpu facilitated changes in Nef that may increase viral pathogenicity
HIV-2
30-80%
Sykes monkey
SIVsyk
30-80%
Sooty mangabey
SIVsmm
SIVgsn
SIVcol
Mantled guereza
SIVs
SIVver
Vervet monkey
SIVlho
Moderately
pathogenic
2-3%
Greater spotnosed monkey
SIVcpz
Chimpanzee
SIVrcm
SIVmnd
Red-capped
mangabey
HIV-1
30-80%
L-Hoest’s monkey
Mandrill
Highly
pathogenic
Acknowledgments
Daniel Sauter
Dominik Hotter
Christian Krapp
Silvia F. Kluge
Christina Stürzel
Jan Münch
Molecular Virology
University of Ulm
Beatrice H. Hahn
University of Pennsylvania
Bernd Baumann
Thomas Wirth
Physiological Chemistry
University of Ulm
Paul M. Sharp
Univ. of Edinburgh
Benoit van Driessche
Carine van Lint
Mol. Biol. & Medicine
University of Brussels
Martine Peeters
Université Montpellier
Oliver T. Fackler
Univ. of Heidelberg
High virulence of HIV-1 & effective spread of group M
Loss of a protective Nef function
Potent tetherin antagonism by Vpu