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: why is the virus so successful?

Strong Glycosylation, conserved domains are „masked“ and only transiently exposed • Camouflage • Highly variable Envelope trimer • Can become invisible • Hide • Immunodeficiency • Cell-Cell Spread • Immune response is too slow

• Viral Antagonists Pancera et al., Nature (2014) • Manipulation of host cells HIV: why is the virus so successful?

Error rate of RT ~ 1 : 10.000 Generation time 1-2 days • Camouflage Billions of progeny virions • Highly variable • Can become invisible • Hide • Immunodeficiency • Cell-Cell Spread • Immune response is too slow • Viral Antagonists • Manipulation of host cells 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 Stevenson, Nat. Med. 2003 • Viral Antagonists • Manipulation of host cells HIV: why is the virus so successful?

Infection of specific • Camouflage 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?

HIV destroys CD4+ helper T-cells • Camouflage • Highly variable • Can become invisible • Hide • Immunodeficiency • Cell-Cell Spread • Immune response is too slow • Viral Antagonists • Manipulation of host 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?

Cytotoxic T cells come too late • Camouflage (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

Removal from nef-defective Wild-type the cell surface control control control

SerinC5 SerinC5 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 Antiviral protein Viral target or “red queen” hypothesis

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 • 35 million people living with HIV • 2.3 million infections per year • about 35 million deaths

Eastern Europe & Central Asia Western Europe 1.2 million North America 570 000 980 000 East Asia & Pacific North Africa 1.2 million Caribbean & Middle East South 440 000 550 000 & South-East Asia 6 million Sub-Saharan Latin America Africa Australia 1.5 million 29.4 million & 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 O Kinshasa: 1959 HIV-1 group P HIV-1 group M 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,…

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

APOBEC3G,X TRIM5,X 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

MLV SIV

HIV HHV-8

XMRV Lassa virus Sauter and Kirchhoff, Curr HIV Res. 2011

Marburg virus Ebola virus VSV JSRV PERV 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

CT Perez-Caballero et al., 2009 Nef

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 CT Nef 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 Nef Uptake globular core

AP2 cellular receptors endosome

2 flexible loops 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 and its HIV-1, SIVcpz Vpu containing SIV precursors

Most SIVs Most primate HIV-2 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 and its HIV-1, SIVcpz Vpu containing SIV precursors

Most SIVs Most primate HIV-2 lentiviruses Vpu facilitated changes in Nef function (Schindler et al., Cell 2006; Schmoekel et al., JVI 2011)

Nef downmodulates TCR-CD3

HIV-1 and its HIV-1, SIVcpz Vpu containing SIV precursors

Most SIVs Most primate HIV-2 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 Viremic HIV-2 infected Sooty mangabeys 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 Loss of Nef-mediated CCR5 CXCR4 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-2, most SIVs HIV-1 and its precursors Nef X Vpu

„Resting“ phenotype Apoptosis, inflammation Vpu facilitated changes in Nef that may increase viral pathogenicity

HIV-2 Moderately pathogenic 30-80% 30-80% Sykes monkey Sooty mangabey

SIVsyk SIVsmm 2-3% SIVcol SIVgsn Greater spot- Mantled guereza nosed monkey SIVs SIVcpz Chimpanzee SIVver SIVrcm

Red-capped Vervet monkey SIVlho SIVmnd mangabey HIV-1 Highly pathogenic 30-80% L-Hoest’s monkey Mandrill Acknowledgments

Daniel Sauter Beatrice H. Hahn Benoit van Driessche Dominik Hotter University of Pennsylvania Carine van Lint Christian Krapp Bernd Baumann Mol. Biol. & Medicine Silvia F. Kluge Thomas Wirth University of Brussels Christina Stürzel Physiological Chemistry Martine Peeters Jan Münch University of Ulm Université Montpellier Molecular Virology Paul M. Sharp Oliver T. Fackler University of Ulm Univ. of Edinburgh Univ. of Heidelberg High virulence of HIV-1 & effective spread of group M

Loss of a protective Nef function

Potent tetherin antagonism by Vpu