Potential Role of Viral Properties in the Pathogenesis of AIDS Frank Kirchhoff Institute of Molecular Virology Ulm Medical Center, Germany 6/11

African primates represent a large reservoir for immunodeficiency viruses and chimpanzees, gorillas and mangabeys transmitted the virus to humans Some SIV-infected monkey species (AGMs, SMs) do not develop disease Bieniasz & Ho Cell 2008

HIV-1 is the result of multiple cross-species transmissions and a recombination event and (Bailes et al., Science 2003; others) Only one of at least four independent transmissions of SIVcpz from chimpanzees and SIVgor from gorillas to humans led to a pandemic

Specific features of HIV-1: Development

Courtesy Paul Spearman degrades CD4 (Willey et al., 1992; Bour et al., 1995) antagonizes tetherin (Neil et al., 2008; Van Damme et al., 2008) inhibits surface expression of CD1d (Moll et al., 2010) down-modulates NTB-A (Shah et al., 2010) Perez-Caballero et al., Cell 2009 Specific features of HIV-1: Vpu Vpu: facilitates the release of fully infectious virions and counteracts innate immunity factors Richard and Cohen, 2010

Specific features of HIV-1: Vpu The evolution of a fully functional Vpu protein may have been a prerequisite for the effective spread of HIV-1 M strains (Sauter et al. 2009) Sauter et al., Human Mutation, in press

Why did HIV-1 M switch from Nef to Vpu to antagonize tetherin? (Jia et al., 2009; Sauter et al., 2009; Zhang et al. 2009) Vpu Tetherin Nef Tetherin TM CT Human tetherin contains a deletion that renders it resistent to Nef SIVcpz & SIV gor HIV-1 M & N

Specific features of HIV-1: Lack of Nef-mediated down-modulation of TCR-CD3 Kirchhoff, Nat. Rev. Micro. (2009)

Specific features of HIV-1: Lack of Nef-mediated down-modulation of TCR-CD3 (Schindler et al., Cell 2006; PLOS Path. 2008; Arhel et al., 2009)

Failure to effectively disrupt the immunological synapse between infected human T cells and APCs (Arhel et al., J. Clin. Invest. 2009) Most primate lentiviruses prevent the interaction between T cells and APCs, whereas HIV-1 just deregulates it Specific features of HIV-1: Lack of Nef-mediated down-modulation of TCR-CD3

Correlates with low numbers of CD4+ T cells in vivo (Schindler et al., PLOS Path., 2008; Khalid et al., unpublished data) SIVsmm infected Sooty mangabeys Viremic HIV-2 infected Human individuals Specific features of HIV-1: Lack of Nef-mediated down-modulation of TCR-CD3

Chlorocebus sabaeus Role of Vpu & Nef-mediated down-modulation of TCR-CD3 in viral pathogenesis? Generation and analysis of an „HIV-1-like“ SIVagm

Wildtype SIVagm (no Vpu, CD3 down) and the „HIV-1-like“ derivative (Vpu, no CD3 down-modulation) maintain high VLs Thus far no marked differences in CD4+ T cell counts or the clinical outcome but increased T cell proliferation in AGMs infected with SIVs expressing the HIV-1 Nef

The emergence of CXCR4-tropic SIVsmm strains is associated with severe CD4 + T cell depletion but not sufficient to induce AIDS in SMs (Milush et al., 2007; Gordon et al., 2007) This lack of disease is associated with double-negative T cells (Milush et al., 2011) Tropism for CXCR4+ T cells: Loss of CD3 down-modulation to facilitate T cell activation Specific features of HIV-1: Links between Vpu, Nef and Env function?

HIV-1 Vpu: CD4, tetherin Nef: no CD3 modulation, weak effect on CD28 and CXCR4 Frequently CXCR4-tropic SIVsmm, SIVagm No Vpu Nef: effective modulation of CD3, CD28 and CXCR4 tetherin antagonism Rarely CXCR4-tropic Deregulates T cell activationBlock T cell activation What we do know: HIV-1 is different from SIVsmm & SIVagm What we dont know: How important are these viral features for the systemic levels of immune activation and the clinical outcome of infection? These properties affect T cell activation in vitro and may be linked

Beatrice H. Hahn Hui Li Frederic Bibollet-Ruche Matthis Kraus (Alabama, USA) Michaela Müller-Trutwin (Paris, France) Martine Peeters (Montpellier, France) Paul Sharp Elisabeth Bailes (Nottingham, UK) Guido Silvestri (Philadelphia, USA) Ulrich Schubert Jörg Votteler (Erlangen, Germany) Paul Bieniasz Theodora Hatziioannou (New York, USA) Cristian Apetrei Ivona Pandrea (Tulane, USA) Christiane Stahl-Hennig Ulrike Sauermann (DPZ, Germany) Donald Sodora (Seattle, USA) Acknowledgments

Institute of Molecular Virology, Ulm Funding: DFG, NIH Thanks for your attention

Virus-host interactions and the virological and clinical outcome of primate lentiviral infections

Increased T cell activation and AICD in virally infected T cells (Schindler et al., 2006) Specific features of HIV-1: Lack of Nef-mediated down-modulation of TCR-CD3

Increased expression of death receptors and activation markers in PBMC cultures Specific features of HIV-1: Lack of Nef-mediated down-modulation of TCR-CD3