Molecular characteristics of HIV-2

Frank Kirchhoff Institute of Molecular VirologyUlm Medical Center, Germany

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HIV-2: Origin

Non-pathogenicHigh VLs

Highlypathogenic

ModeratelyPathogenic

80% LTNPs, lowVLs

Only HIV-2 groups A and B have spread significantly in humans

• Vpx: antagonizes SAMHD1 (Laguette et al., 2011; Hrecka et al., 2011) • No Vpu: CD4 degradation and tetherin antagonism in HIV-1• Nef: effective down-modulation of TCR-CD3 and CD28

HIV-2: molecular characteristics

HIV-2: absence of Vpu

Perez-Caballero et al., 2009

• HIV-1 M strains use Vpu to antagonize tetherin• HIV-2 A uses Env• Unclear whether HIV-2 B-H counteract tetherin

Nef, Vpu Nef, EnvNef

HIV-2: absence of Vpu

Perez-Caballero et al., 2009

• HIV-1 M strains use Vpu to antagonize tetherin• HIV-2 A uses Env• Unclear whether HIV-2 B-H counteract tetherin

Nef, Vpu Nef, EnvNef

HIV-2: absence of Vpu

Perez-Caballero et al., 2009

• HIV-1 M strains use Vpu to antagonize tetherin• HIV-2 A uses Env• Unclear whether HIV-2 B-H counteract tetherin

???

Nef, Vpu Nef, EnvNef

HIV-2: absence of Vpu

Perez-Caballero et al., 2009

• HIV-1 M strains use Vpu to antagonize tetherin• HIV-2 A uses Env• Unclear whether HIV-2 B-H counteract tetherin

HIV-2: effective Nef-mediated down-modulation of TCR-CD3 and CD28

HIV-1 SIVcpz

CD3

SIVsmmHIV-2

CD3

chronic activationdeath of T cellsAIDS

little activationT cells survivetolerance

Antigenpresenting cell Resting T cellAntigenpresenting cell Activated T cellActivation induced

cell death

Antigenpresenting cell Resting T cellAntigenpresenting cell “Resting“ T cell Antigenpresenting cell “Resting“ T cell

Infected PBMC

HIV-2: effective Nef-mediated down-modulation of TCR-CD3 and CD28

Disruption of the immune synapse between vially infected T cells and APCs (Arhel et al., J. Clin. Invest. 2009)

HIV-2 prevents the interaction between T cells and APCs, whereas HIV-1 just deregulates it

HIV-2: effective Nef-mediated down-modulation of TCR-CD3 and CD28

Inefficient Nef-mediated downmodulation of CD3 correlates with loss of CD4+T cells in natural SIV infection (Schindler et al. PLOS Path. 2008)

Nef may protect the natural hosts of SIV against the loss of CD4+ T cells by down-modulation of TCR-CD3 to prevent activation-induced cell death

Downregulation of CD3 by HIV-2 Nef does not protect against disease (Feldmann et al., JVI 2009) BUT Most HIV-2-infected individuals had low VLs and high CD4+ T cell counts and the nef alleles were only examined using expression constructs in Jurkat T cells The efficiency of TCR-CD3 downregulation by Nef correlated with low levels of immune activation in vivo

Downregulation of CD3 by HIV-2 Nef does not protect against disease (Feldmann et al., JVI 2009) BUT Most HIV-2-infected individuals had low VLs and high CD4+ T cell counts and the nef alleles were only examined using expression constructs in Jurkat T cells The efficiency of TCR-CD3 downregulation by Nef correlated with low levels of immune activation in vivo

Downregulation of CD3 by HIV-2 Nef does not protect against disease (Feldmann et al., JVI 2009) BUT Most HIV-2-infected individuals had low VLs and high CD4+ T cell counts and the nef alleles were only examined using expression constructs in Jurkat T cells The efficiency of TCR-CD3 downregulation by Nef correlated with low levels of immune activation in vivo

Analysis of nef alleles from 20 viremic (VL >500/ml) and 16 non-viremic (<500/ml) HIV-2-infected individuals (Feldmann et al., 2009; Guillon et al., 1998; Blaak et al., 2008)

Nef-mediated downmodulation of TCR-CD3 correlates with high numbers of CD4+ T cells in viremic HIV-2-infected individuals

All Non-viremic Viremic

All Non-viremic Viremic

Nef-mediated downmodulation of CD28 correlates with high numbers of CD4+ T cells in viremic HIV-2-infected individuals

Other Nef functions (modulation of CD4 & MHC-I, enhancement of infectivity & replication) did not correlate with the CD4+ T cell counts in infected individuals

T cells infected with viruses containing HIV-2 nef genes express low levels of death receptors and activation markers

PBMC cultures infected with viruses containing HIV-2 nef genes express low levels of type I interferons

• Effective infection of MPs and DCs by Vpx-mediated degradation of SAMHD1• Antagonism of human tetherin by the Envelope glycoprotein (HIV-2 group A; B-H unclear)• Potent suppression of T cell activation by Nef-mediated down-modulation of TCR-CD3 & CD28

Characteristics of HIV-2: Summary

(Preliminary) conclusions

• Tetherin antagonism may play a role in the spread of HIV-2

• Nef may help viremic HIV-2-infected individuals to maintain normal CD4+ T cell counts by preventing T cell activation & apoptosis

• Effective infection of MPs and DCs by Vpx-mediated degradation of SAMHD1• Antagonism of human tetherin by the Envelope glycoprotein (HIV-2 group A; B-H unclear)• Potent suppression of T cell activation by Nef-mediated down-modulation of TCR-CD3 & CD28

Characteristics of HIV-2: Summary

(Preliminary) conclusions

• Tetherin antagonism may play a role in the spread of HIV-2

• Nef may help viremic HIV-2-infected individuals to maintain normal CD4+ T cell counts by preventing T cell activation & apoptosis

Efficient Nef-mediated downmodulation of TCR-CD3 is associated with high CD4+ T cell counts in viremic HIV-2-infected individuals

Mohammad Khalid,1 Jerome Feldman,2 Rob A. Gruters,3 Hetty Blaak,3 Marchina E. van der Ende,4 Sarah Rowland-Jones,5,6

Albert D. Osterhaus,3 and Frank Kirchhoff1

1Institute of Molecular Virology, University Clinic Ulm, Germany; 2Unité Virus et Immunité, Institut Pasteur, Paris, France; 3Dep. of Virology and 4 Dep. of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands; 5MRC Laboratories, Fajara, The Gambia; 6MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom

Deutsche Forschungsgemeinschaft