Potential Role of Viral Properties in the Pathogenesis of AIDS
Frank Kirchhoff Institute of Molecular Virology Ulm Medical Center,
Germany 6/11
Slide 2
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
Slide 3
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
Slide 4
Specific features of HIV-1: Development
Slide 5
Slide 6
Slide 7
Slide 8
Slide 9
Slide 10
Slide 11
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
Slide 12
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
Slide 13
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
Slide 14
Specific features of HIV-1: Lack of Nef-mediated
down-modulation of TCR-CD3 Kirchhoff, Nat. Rev. Micro. (2009)
Slide 15
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)
Slide 16
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
Slide 17
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et al., PLOS Path., 2008; Khalid et al., unpublished data) SIVsmm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
Slide 18
Chlorocebus sabaeus Role of Vpu & Nef-mediated
down-modulation of TCR-CD3 in viral pathogenesis? Generation and
analysis of an HIV-1-like SIVagm
Slide 19
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
Slide 20
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?
Slide 21
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
Slide 22
Beatrice H. Hahn Hui Li Frederic Bibollet-Ruche Matthis Kraus
(Alabama, USA) Michaela Mller-Trutwin (Paris, France) Martine
Peeters (Montpellier, France) Paul Sharp Elisabeth Bailes
(Nottingham, UK) Guido Silvestri (Philadelphia, USA) Ulrich
Schubert Jrg 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
Slide 23
Institute of Molecular Virology, Ulm Funding: DFG, NIH Thanks
for your attention
Slide 24
Virus-host interactions and the virological and clinical
outcome of primate lentiviral infections
Slide 25
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
Slide 26
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
