Potential Role of V iral P roperties in the Pathogenesis of AIDS
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Potential Role of Viral Properties in the
Pathogenesis of AIDS
Frank Kirchhoff Institute of Molecular VirologyUlm Medical Center, Germany
6/11
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African primates represent a large reservoir for immunodeficiency virusesand chimpanzees, gorillas and mangabeys transmitted the virus to humans
Some SIV-infected monkey species (AGMs, SMs) do not develop disease
Bieniasz & HoCell 2008
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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
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Specific features of HIV-1: Development
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Specific features of HIV-1: Development
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Specific features of HIV-1: Development
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Specific features of HIV-1: Development
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Specific features of HIV-1: Development
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Specific features of HIV-1: Development
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Specific features of HIV-1: Development
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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
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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
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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
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Specific features of HIV-1: Lack of Nef-mediated down-modulation of TCR-CD3
Kirchhoff, Nat. Rev. Micro. (2009)
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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)
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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
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Correlates with low numbers of CD4+ T cells in vivo(Schindler et al., PLOS Path., 2008; Khalid et al., unpublished data)
SIVsmm infectedSooty mangabeys
Viremic HIV-2 infectedHuman individuals
Specific features of HIV-1: Lack of Nef-mediated down-modulation of TCR-CD3
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Chlorocebus sabaeus
Role of Vpu & Nef-mediated down-modulation of TCR-CD3 in viral pathogenesis?
Generation and analysis of an „HIV-1-like“ SIVagm
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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 outcomebut increased T cell proliferation in AGMs infected with SIVs expressing the HIV-1 Nef
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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?
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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 CXCR4tetherin antagonism
• Rarely CXCR4-tropic
Deregulates T cell activation Block 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
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Beatrice H. Hahn Hui Li
Frederic Bibollet-RucheMatthis Kraus
(Alabama, USA)
Michaela Müller-Trutwin (Paris, France)
Martine Peeters(Montpellier, France)
Paul SharpElisabeth Bailes
(Nottingham, UK)
Guido Silvestri(Philadelphia, USA)
Ulrich Schubert Jörg Votteler
(Erlangen, Germany)Paul Bieniasz
Theodora Hatziioannou(New York, USA)
Cristian ApetreiIvona Pandrea(Tulane, USA)
Christiane Stahl-HennigUlrike Sauermann(DPZ, Germany)
Donald Sodora (Seattle, USA)
Acknowledgments
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Institute of Molecular Virology, Ulm
Funding: DFG, NIH
Thanks for your attention
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Virus-host interactions and the virological and clinical outcome of primate lentiviral infections
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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
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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