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HIV-2 infection: a model for protective immunity against HIV?

HIV-2 infection: a model for protective immunity against HIV?. Sarah Rowland-Jones, Nuffield Department of Medicine, Oxford University, UK. Caio: community cohort in Casheu Region of Guinea Bissau (ART from 2007) 4000 adults: 7.9% HIV-2+ in 1989 HIV-2 prevalence now 4%, HIV-1 3.7%

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HIV-2 infection: a model for protective immunity against HIV?

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  1. HIV-2 infection: a model for protective immunity against HIV? Sarah Rowland-Jones, Nuffield Department of Medicine, Oxford University, UK

  2. Caio: community cohort in Casheu • Region of Guinea Bissau (ART from 2007) • 4000 adults: 7.9% HIV-2+ in 1989 • HIV-2 prevalence now 4%, HIV-1 3.7% • (van Tienen, J.AIDS 09) MRC Laboratories, the Gambia • MRC GUM clinic, Fajara: • ~3000 HIV-1/-2/dual patients • ART available since 2004 • Clinic closed in 2009 Caió field station and community cohort M. Cotten

  3. Undetectable HIV-2 plasma viral load is stable and predicts normal survival in Caio Follow up of 133 HIV-2 infected and 158 HIV-uninfected people in Caio 1991 – 2006 • 37% HIV-2 elite controllers in Caio community cohort (1991) • Plasma viral load stable for over a decade • Overall HIV-2 mortality approximately 2x uninfected controls • For subjects over 60 years old, survival is unaffected by HIV-2 status (Schim van der Loeff et al., Retrovirology, 2010)

  4. Systemic immune activation is a feature of HIV-2 infection and is directly related to viral load HLA-DR CD38 CD4/CD8 HLA-DR/CD38 expression HIV-2 patients: N=107 Leligdowicz et al, JID, 2010

  5. Distinct HLA and KIR associations with HIV-2 susceptibility/disease outcome • Studies performed in the Caio cohort (ethnically homogeneous), 150 HIV-2 infected subjects with 328 HIV negative controls: (L-M Yindom et al, JVI 10) • Sequence-based typing with Mary Carrington’s lab, NCI • Strong association of HLA-B*08 with susceptibility to HIV-2 infection (P = 0.003, OR = 2.20, CI = 1.31 – 3.70) • KIR2DL2 and KIR2DS2 + C1/x associated with protection against HIV-2 infection (P = 0.04, OR = 0.66, P = 0.03, OR = 0.63, CI = 0.41 – 0.95) • HLA-B*15 is strongly associated with low absolute CD4 count (P = 0.003)and high mean log VL: related to presentation of envelope (and not gag) epitopes? (Godelieve de Bree)

  6. Potent and broad neutralising antibody responses in HIV-2 infection • HIV-2-infected subjects have very strong neutralising Ab responses, which sometimes neutralise HIV-1 (Weiss, AIDS 1988, Bjorling, Virology 1993, Rodriguez JVI 07) • Autologous neutralisation appears stable over time – limited envelope evolution? (Shi, JGV, 05) • nAbs in HIV-2 infection show greater breadth than in HIV-1 infection, regardless of disease stage (Rodriguez, JVI 2007) • Broad and potent neutralising activity in 35/40 Caio donors : several logs higher than seen in HIV-1 infection (de Silva, ms submitted) • BUT no correlation between presence, magnitude or breadth of nAb response with disease status(weak positive correlation with viral load) (Rodriguez, JVI 2007)(de Silva,submitted)

  7. HIV-2-specific CD4+ T cell function is preserved in non-progressors IFN-g IL-2 IFN-g & IL-2 Melody Duvall et al, JI 2006 Subjects with CD4 >28% Striped bars: HIV-1 Solid bars: HIV-2

  8. Gag SFU Pol SFU Acc SFU Env SFU Nef SFU In contrast to HIV-1 infection, HIV-2+ controllers have very strong T-cell responses, targeting gag p26 VL <100 (N=31) VL >100 (N=33) Elispot responses to overlapping peptides from A clade HIV-2 gag proteome

  9. HIV-2 gag contains a “protective” T-cell epitope Peptide 46 - MHR region of gag p26 Target for CD4+ responses, HLA-DR*1302-restricted Also target for CD8+ responses, including B14 and B40-restricted 20 Patients with Peptide 046-specific responses have a lower VL than those who do not(p=0.05) Leligdowicz et al, JCI, 2007

  10. Elite controllers with HIV-2 have significantly stronger Gag-specific CD8+ T-cell responses than progressors Responses tested by ICS stimulated by pooled HIV-2 clade A gag peptides CD8 CD4 responses CD8 responses (two-tailed Mann Whitney-U test) Thushan de Silva, in preparation

  11. What are the distinct qualities of HIV-2-specific CD8+ T-cells? • HIV-2-specific CTL are at an earlier stage of differentiation than HIV-1-specific CTL – better able to proliferate, despite expressing high levels of PD-1 (Leligdowicz, EJI 2010) • Persist at very high frequencies (up to 10% of all CD8+ T-cells), despite undetectable VL • High functional avidity: produce large amounts of anti-viral cytokines at low levels of antigen • CTL from controllers do not have higher perforin levels than CTL from progressors (Thushan de Silva, in preparation) • Conservation of T-cell receptor usage with “public motifs” (Eirini Moysi, in preparation)

  12. HIV-2-specific CD8+ T cell clones show remarkably high functional avidity

  13. HIV-2 immunity: conclusions • HIV-2 provides an important human model of control of a potentially pathogenic retrovirus • HIV-2 infection is not generally attenuated but yields a high proportion of LTNPs, whereas progressors develop AIDS in a similar way to people with HIV-1 infection • “Non-progression” is associated with good quality CD4+ T-cell help, high magnitude, polyfunctional, early-differentiated CD8+ T-cell responses, but not broadly neutralising antibody responses • Control of viraemia is strongly associated with T-cell responses to a single highly conserved region in the capsid protein • T-cells responding to this region are polyfunctional, show conserved TCR usage and are of unusually high avidity • Is this the kind of immune response we want from an HIV vaccine?

  14. How does HIV-2 infection differ from SIVsm in the natural host? • Most SIVsm infected monkeys have a normal lifespan with no signs of immunodeficiency • Although the sequence of HIV-2 is very similar to SIVsm, there are significant differences from SIVsm model of naturally attenuated SIV infection in sooty mangabeys • HIV-2 infected LTNPs have low plasma viral load and strong immune responses • SIVsm-infected monkeys have very high viral loads, normal T-cell turnover, absent immune activation and weak immune responses (Silvestri, 03, Paiardini, 09) • Immune activation is low in LTNPs but increased in progressors with HIV-2 infection to a level comparable with HIV-1 (Sousa, JI 02)

  15. Acknowledgements MRC HIU, Oxford Sabelle Jallow Thushan de Silva Eirini Moysi Yannis Hodges Godelieve de Bree Tao Dong Guillaume Stewart-Jones Andrew McMichael NCI, Frederick Pat Martin Mary Carrington MRC Laboratories, the Gambia Assan Jaye Aleks Leligdowicz Matt Cotten Victor Nuvor Louis-Marie Yindom Melody Duvall Jerome Feldmann Clayton Onyango Irfan Zaidi Ingrid Peterson Tim Vincent Akram Zaman Ramu Sarge-Njie Carlos da Costa Abraham Alabi Beatrice Ondondo Kevin Peterson Carla van Tienen Maarten Schim Thushan de Silva Toyin Togun Robert Walton Hilton Whittle Samuel Nyamweya HIV lab, clinic and field staff All the members of the Caio cohort Bandim project, Bissau Peter Aaby LSHTM Natasha Larke ShabbarJaffar UCL, London Robin Weiss National Institute for Infectious Diseases, Tokyo Masaru Yokoyama, Hironori Sato Osaka University Haihan Song, Emi Nakayama, Tatsuo Shioda VRC, NIH Jason Brenchley Danny Douek Rick Koup

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