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? 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? 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 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,… 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