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Sarah Rowland-Jones Nuffield Department of Medicine, Oxford University, UK

What can we learn about HIV pathogenesis from different models of natural control of HIV/SIV infection?. Sarah Rowland-Jones Nuffield Department of Medicine, Oxford University, UK. Approaches to defining protective immunity against HIV infection. Learn from other successful human vaccines

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Sarah Rowland-Jones Nuffield Department of Medicine, Oxford University, UK

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  1. What can we learn about HIV pathogenesis from different models of natural control of HIV/SIV infection? Sarah Rowland-Jones Nuffield Department of Medicine, Oxford University, UK

  2. Approaches to defining protective immunity against HIV infection • Learn from other successful human vaccines • Develop and test a successful HIV vaccine in humans or SIV vaccine in monkeys • Study individuals with a relatively good outcome from an encounter with HIV/SIV • Exposed seronegatives • Long-term non-progressors/elite controllers with HIV-1 infection • Monkeys with naturally attenuated SIV infection (such as SIVsmm in sooty mangabeys) • Humans with naturally attenuated HIV-2 infection

  3. Delayed disease progression in HIV-1 infection • Natural history of HIV-1 infection without therapy follows a normal distribution, with a median time to AIDS around 10-11 years in most cohorts (regardless of ethnic origin or infecting clade) • Long-term non-progressors (LTNPs) defined as survivors with HIV-1 infection for >7-10 years, no therapy, no symptoms and stable CD4+ T-cell count > 500mm3; represent around < 1-5 % of cohorts • “Elite controllers” defined as HIV-1 infected individuals with plasma VL <50 copies/ml for over one year without ART: represent 0.35-0.8% of most cohorts • “Viraemic controllers”: as above but with pVL <2000 copies/ml • Some but not complete overlap: controllers may progress to AIDS even whilst maintaining low viral load, LTNPs may have high viral load: most people in both groups eventually develop disease • US Department of Defense Natural History study of >4500 subjects: 0.55% were elite controllers, who maintained viraemic control for a median of 846 days, significantly better clinical outcome than viraemic controllers (3.34%): 2.04% LTNP(10)s – significantly longer survival than LTNP(7s) (Okulicz, JID 09)

  4. What are the mechanisms of spontaneous viral control in HIV-1 infection? • Mechanisms of viral control are heterogeneous • A minority are infected with attenuated virus, with mutations in nef/LTR (e.g the Sydney Blood Bank cohort) (Deacon, Science 95) • Elite controllers have lower pro-viral load and virus is difficult to culture, although activated cells are susceptible to exogenous HIV infection (Julg, CID 10) • Strong HLA class I associations, especially HLA-B27 (~20% controllers), HLA-B*5701/B*5703 (~50% of controllers), HLA-B51: also -35 mutation in HLA-C promoter, associated with increased HLA C expression (Carrington, Science 99, Fellay, Science 07, Carrington NG 09) • Additional protective effect from KIR3DS1 in association with Bw4 HLA types (Martin, Nat. Gen. 02, 06) • Other host genetic polymorphisms (e.g. CCR5-D32, CCR2-64I) with more modest impact on progression

  5. Features of the HIV-1-specific immune response associated with viral control • Immune activation lower in LTNPs than progressors but higher than HIV- controls (Hunt, JID 08) • LTNPs don’t have stronger or broader CTL responses than progressors and tend to have low nAb titres • Tend to have preserved HIV-specific CD4+ T-cell responses (including IL-2 secretion) (Rosenberg, Science 97, Boaz, JI 02) • Presence of CTL responses to 3 or more epitopes in gag correlates with lower viral load(Kiepiela, NM 07) • Noprotective T-cell epitopes identified • How do the beneficial HLA types confer protection? Not clear, possibly through selection of escape variants with a significant fitness cost (Martinez-Picardo, JVI, 06, Miura, JVI 09) or through generation of CTL with enhanced cytolytic ability (Migueles, Immunity 08)

  6. Features of the HIV-specific CTL response associated with viral control: II • CTL from LTNPs more likely to be polyfunctional and produce MIP-1b(Betts, Blood, 06) • Progressors more likely to have CTL expressing markers of senescence (CD57) or exhaustion (PD-1) (Brenchley, Blood 02, Day, Nature 07) • HIV-specific CTL from LTNPs more likely to be able to proliferate and show higher levels of Perforin (Migueles NI 02)(Hersperger, PLoSP 10) and Granzyme B (Migueles, Immunity 08) • CTL from LTNPs likely to be of high avidity (Almeida, JEM 07, Blood 09) • Certain T-cell receptors may convey an advantage: e.g. with the ability to contain escape mutation (Dong JEM 04) or with unusually high avidity • Selection of CTL escape mutations in elite controllers suggests ongoing viral replication and evolution (Miura, JVI 09)

  7. SIV in natural hosts: the sooty mangabey model • Natural hosts of SIV include the African green monkey and the sooty mangabey (from West Africa) • SIVsmm has entered humans on several occasions, forming different clades of HIV-2, and has also given rise to SIV mac strains • Most SIVsm infected monkeys have a normal lifespan with no signs of disease • Occasionally develop low CD4 count, but not associated with clinical immunodeficiency • Kinetics of viral replication similar to that of pathogenic SIV/HIV • Primary infection associated with CD4+ depletion in GALT, similar to that seen in pathogenic SIV • Persistently high viral loads (104 – 106/ml), with low immune activation, normal T-cell turnover and weak immune responses (both T-cell and ab) (Paiardini, 09)

  8. CD4 CD8 B cell The Battle of the Immune system in HIV-1 infection CD4 T cell exhaustion Functional CD4 T cell help & regulation Proliferation < Apoptosis CD4 and CD8 T cell exhaustion CD8 T cells HLA type-dependent VL driven Superinfections Loss of Tregs Neutralizing Ab Rise in immune activation Rise in VL Viremia control Viral Escape Loss of CD8 T cells Loss of neutralizing Abs

  9. Causes of immune activation in HIV/SIV infection • HIV antigenic stimulation • HIV gene products • Env: gp120 binds CD4/co-receptors, leading to activation • Nef: triggers transcription (97% identical to αCD3 T cell activation) • Nef in SIVs • Downregulation of CD3-TcR  protection from immune activation (BUT – SIV mac) • Ability to downregulate CD3-TcR is lost in HIV-1 Nef (retained in HIV-2) • Low Treg levels • In SIVagm-infected AGMs: high Tregs • Increased TGFβ, IL-10  attenuated immune activation • Co-infection, including CMV infection • As CD4 T cell levels decline, latent viruses are reactivated • Mucosal barrier integrity/CCR5+ CD4 T cell depletion • Microbes translocate across the disrupted GI wall as CD4 T cells are depleted • LPS activates innate immune system via TLR signaling on macrophages/DCs • Proinflammatory state established • Induction of innate immune systemleading to functional impairment of T cells • Suppressive effect of type I interferon produced by pDC

  10. Immune activation increases with disease progression in HIV-1 infection Grossman et al, Nature Medicine 12, 289 - 295 (2006)

  11. Immune activation is low in SIV-infected natural host monkeys Paiardini et al, Ann. Rev. Med. 09

  12. HIV-2:a naturally attenuated human retrovirus infection? • 1983 – HIV-1 isolated • Evolved from SIVcpz • Group M cross-species transmission: • ~1930 +/- 15 years • 1986 – HIV-2 isolated • Evolved from SIVsm • Endemic amongst sooty mangabeys (Tau forest, Cote d’Ivoire) • Each subtype represents a distinct cross-species transmission: • Probably 8 separate entries into humans • ~1940 +/- 16 years (Lemey, PNAS 03) • Guinea Bissau suggested as epicentre of HIV-2 epidemic in West Africa • Rapid spread began in 1960-70 • Coincides with war of independence (1963-74) • Epidemiological linkage with Portugal • First HIV-2 cases in Europe recorded in Portuguese war veterans • Lisbon has the largest number of HIV-2 cases in Europe • HIV-2 found in Angola, Mozambique, Goa • Also reported in India, Brazil, S. Korea, Japan

  13. Why study HIV-2 infection? • ~1 million people infected in West Africa • 15-20% HIV-2-infected people develop AIDS and could benefit from ART, but effective viral suppression with ART is much harder to achieve than for HIV-1 - intrinsic resistance to NNRTIs, fusion inhibitors and some protease inhibitors • Does HIV-2 protect against HIV-1 infection? (Travers, Science 1995): protection not found in three other studies - probably a risk factor in Caio (Schim van der Loeff, AIDS 2001) • Majority of infected people have a normal lifespan and show no signs of immunodeficiency - natural human model of attenuated HIV infection • Progressors (15-20%) clinically indistinguishable from people with HIV-1 • Responses to HIV-2 in non-progressors resemble those currently desired from an HIV-1 vaccine

  14. How does the natural history of HIV-2 infection differ from HIV-1? • Proviral load at different disease stages is similar to HIV-1, but plasma viral load is much lower (Berry, 1998, Popper, 2000) • Disease progression is predicted by plasma VL (Whittle, 1992, Berry 2003) and serum 2m (Jaffar, 2005) but NOT by CD4 count/% (Jaffar, 2010) • Rates of progression similar between HIV-1 and HIV-2 for a given plasma VL (Gottlieb, 2002) (Hansmann, 2005) • Progression to AIDS occurs in a minority, estimated at 20% in the Caio cohort (Jaffar, 2010) • Clinical features are indistinguishable from AIDS caused by HIV-1 (Martinez-Steele, 2006) • Age is NOT a risk factor for disease progression • Life expectancy of older people (55-80 yrs) with HIV-2 same as uninfected population (Poulsen, 1997) • Thus HIV-2 does not have a generally attenuated phenotype, but leads to a very high proportion of LTNPs

  15. Survival with HIV-2 infection in the Caio cohort • Follow up of 133 HIV-2-infected subjects and 158 HIV uninfected controls in Caio between 1991 and 2006 (S. Jaffar et al, Retrovirology 2010) • Overall mortality rate per 100 person years was 4.6 for the HIV-2+ subjects and 2.2 for the controls • For subjects over 60 years old, survival is unaffected by HIV-2 status • Survival shows strong inverse correlation with plasma viral load, no independent relationship with %CD4 cells • Plasma viral load was stable in the non-progressors for over a decade

  16. 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

  17. Strong immune responses are associated with HIV-2 control • 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 (Duvall, JI 06, EJI 08), high magnitude, polyfunctional CD8+ T-cell responses (Leligdowicz, JCI 07), and preserved innate responses (Nuvor, JVI 06) • Control of viral load is strongly associated with T-cell responses to a single highly conserved region (MHR) in the capsid protein (Leligdowicz, JCI 07) • T-cells responding to this region are of unusually high avidity with restricted T-cell receptor usage, and do not select escape variants (Leligdowicz, EJI 10) • Is this the kind of immune response we need from an HIV-1 vaccine?

  18. 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

  19. Characteristics of T-cell responses to the “protective” HIV-2 peptide p46 • T-cells target the Major Homology Region (MHR) • 20- region in capsid domain of Gag • Plays a critical role in particle assembly • Immunogenic: contains several T-cell epitopes in HIV-1 • Highly conserved among most retroviruses • Good potential for resistance to escape mutation • T-cells targeting this region show: • Unusually high avidity (several log orders greater than for most virus-specific T-cells) • Oligoclonal TCR usage (selection of Vb17) • Early differentiation phenotype: proliferate well, not “exhausted” (despite long infection history) • Don’t select viral escape variants (Leligdowicz, EJI 10)

  20. Comparison of HIV-1/HIV-2/SIVsmm models of viral control • SIVsmm: Stable phenotype, 100% animals • high viral loads • Weak immune responses • Low/absent immune activation • HIV-1 elite control: Very rare: Stable phenotype?? • Low viral load/viral replication • Moderate immune responses, high quality gag-specific CTL, select escape mutations • Low but detectable immune activation • HIV-2 elite control: Stable phenotype in ~80% subjects • Low viral load/viral replication • Very strong immune responses, high quality, high avidity gag peptide-specific CTL, no viral escape • Low but detectable immune activation

  21. ~ Thank you ~

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