HIV-2 infection: a model for protective immunity

against HIV?

Sarah Rowland-Jones,Nuffield Department of Medicine,

Oxford University, UK

M. Cotten

MRC Laboratories, the Gambia

Caió field station and community cohort

MRC GUM clinic, Fajara:~3000 HIV-1/-2/dual patients • ART available since 2004• Clinic closed in 2009

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)

Undetectable HIV-2 plasma viral load is stable and predicts normal survival in

Caio

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)

Follow up of 133 HIV-2 infected and 158 HIV-uninfected people in Caio 1991 – 2006

CD38

HLA

-DR

 Activation markers CD4+ CD8+

HLA-DR+ rs=0.56p<0.0001

rs=0.46p<0.0001

CD38+ rs=0.27p=0.0053

rs=0.45p<0.0001

CD38+HLA-DR+ rs=0.64p<0.0001

rs=0.59p<0.0001

10 100 1,000 10,000 100,000 1,000,0000.0

10.020.030.040.050.060.070.080.0

HIV-2 VL and CD4_HLA-DR+

Log HIV-2 virus load

% C

D4_

HLA

-DR+

10 100 1,000 10,000 100,000 1,000,0000.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

HIV-2 VL and CD4_CD38+

Log HIV-2 virus load

% C

D4_

CD38

+

10 100 1,000 10,000 100,000 1,000,0000.05.0

10.015.020.025.030.035.040.045.050.0

HIV-2 VL and CD4_HLA-DR+CD38+

Log HIV-2 virus load

% C

D4_

HLA

-DR+

CD38

+

10 100 1,000 10,000 100,000 1,000,0000.0

10.020.030.040.050.060.070.080.090.0

100.0

HIV-2 VL and CD8_HLA-DR+

Log HIV-2 virus load

% C

D8_

HLA

-DR+

10 100 1,000 10,000 100,000 1,000,0000.0

10.020.030.040.050.060.070.080.090.0

100.0

HIV-2 VL and CD8_CD38+

Log HIV-2 virus load

% C

D8_

CD38

+

10 100 1,000 10,000 100,000 1,000,0000.0

10.020.030.040.050.060.070.080.090.0

HIV-2 VL and CD8_HLA-DR+CD38+

Log HIV-2 virus load

% C

D8_

HLA

-DR+

CD38

+

Systemic immune activation is a feature of HIV-2 infection and is directly related to viral

load

Leligdowicz et al, JID, 2010

CD4/CD8 HLA-DR/CD38 expression

HIV-2 patients: N=107

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)

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)

IFN-g

IL-2

IFN-g &

IL-2

HIV-2-specific CD4+ T cell function

is preserved in non-progressorsMelody Duvall et al, JI 2006

Striped bars: HIV-1Solid bars: HIV-2

Subjects with CD4 >28%

Gag SFU Pol SFU Acc SFU Env SFUNef SFU

VL <100 (N=31) VL >100 (N=33)

In contrast to HIV-1 infection, HIV-2+ controllers have very strong T-cell responses,

targeting gag p26

Elispot responses to overlapping

peptides from A clade HIV-2 gag

proteome

HIV-2 gag contains a “protective” T-cell epitope

Patients with Peptide 046-specific responses have a lower VL than those who do not (p=0.05) Leligdowicz et al, JCI, 2007

20 Peptide 46 - MHR region of gag p26Target for CD4+ responses, HLA-DR*1302-restrictedAlso target for CD8+ responses,including B14 and B40-restricted

Elite controllers with HIV-2 have significantly stronger Gag-specific CD8+ T-cell responses

than progressors

CD8 CD4 responsesCD8 responses

(two-tailed Mann Whitney-U test)Thushan de Silva, in preparation

Responses tested by ICS stimulated by pooled HIV-2 clade A gag

peptides

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)

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

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?

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)

AcknowledgementsMRC Laboratories, the GambiaAssan Jaye Aleks LeligdowiczMatt Cotten Victor Nuvor Louis-Marie Yindom Melody DuvallJerome Feldmann Clayton OnyangoIrfan Zaidi Ingrid PetersonTim Vincent Akram ZamanRamu Sarge-Njie Carlos da CostaAbraham Alabi Beatrice OndondoKevin Peterson Carla van TienenMaarten Schim Thushan de SilvaToyin Togun Robert WaltonHilton Whittle Samuel NyamweyaHIV lab, clinic and field staffAll the members of the Caio cohort Bandim project, Bissau Peter Aaby

NCI, FrederickPat MartinMary Carrington

VRC, NIHJason BrenchleyDanny DouekRick Koup

MRC HIU, OxfordSabelle JallowThushan de SilvaEirini MoysiYannis HodgesGodelieve de BreeTao DongGuillaume Stewart-JonesAndrew McMichael

UCL, LondonRobin WeissNational

Institute for Infectious Diseases, TokyoMasaru Yokoyama,Hironori SatoOsaka UniversityHaihan Song, Emi Nakayama, Tatsuo Shioda

LSHTMNatasha LarkeShabbar Jaffar