Primate models of SIV infection: Differenct susceptibility of African green monkeys and macaques to develop AIDS

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1 Les Pensières Animal Models, 2011 Primate models of SIV infection: Differenct susceptibility of African green monkeys and macaques to develop AIDS Michaela Müller-Trutwin Unité de Régulation des Infections Rétrovirales

2 HIV infection Worldwide: 2.6 million new infections per year 34 million people infected (> 99.6% due to HIV-1 M) 2 million victimes per year 9 Million people living with HIV with need of treatment but no access to it In France: 6000 new infections per year About 35% of HIV-infected individuals are not aware of their infection --> risk of transmission --> risk of progression towards AIDS

3 Three profiles of HIV-1 infection «normal» progression rapid progression Long term non progression (LTNP) Viremia T CD4 + T CD4 + Viremia acute phase 7 years 3 years asymptomatic phase AIDS acute phase 3 years AIDS acute phase >10 years asymptomatic phase LTNP (Long term non progressors) :1-5 % Elite LTNP : 0.1% Controlers (Ctrls) : 0.5% Elite Controlers (EC) : 0.25% LTNP ELTNP EC Ctrl Grabar S, AIDS, 2008

4 CD4 T Cell Depletion is linked more closely to Immune Activation than to viral load Long term non progressors (LTNP)/ HIV Controlers / HIV-2? Efficient anti-viral responses Low viremia? Low viremia? High viremia Low generalised T cell activation Slow progression to AIDS Liovat AS et al, CHIR, 2009

5 HIV-1 infection & replication Viral proteins gp120, Nef Loss of Th17 cells, intestinal barrier disruption Ag stimulation Inflammation Microbial translocation Reactivation of latent infections (CMV) chronic immune activation TGF-β1 => Fibrosis => desorganisation of lymphoid organs structure T CD4 cell apoptosis Exhaustion, premature aging of the immune system AIDS Chronic immune activation associated pathologies Adapted from Appay, J Pathol. 2008

6 Residual generalized T cell activation in patients with controlled viremia Activation chronique healthy HIV-infected treated S. Deeks, XVIII Interna0onal AIDS Conference, 2010 Elite controllers have higher chronic T cell activation levels than healthy donors (Hunt PW et al JID, 2008)

7 Early host response is predictive of outcome of infection setpoint T cell activation T CD8 + DR + CD acute phase chronic phase Rapid progressors Normal progressors LTNP/Ctrl/EC T cell activation level at seroconversion predicts disease progression profile (Hazenberg et al AIDS 2000; Deeks et al, JID, 2004)

8 What determines the level of generalized T cell activation early on in HIV infection? Study of early virus host interactions in blood and lymphoid tissues Non human primates infected by SIV (physiopathology, immune responses)

9 Accidental and natural hosts of SIV Daniel et al, Science, st SIV : SIVmac macaque macaque AIDS SIV positive in captivity SIV negative in the natural habitat : sooty mangabey HIV-2 African green monkey mandrill chimpanzee HIV-1 M : 40 natural hosts species

10 SIVmac / Macaque: Three profiles of disease progression normal progression rapid progression LTNP Viremia T cell activation TCD weeks years 1-6 months >3 years asymptomatic phase AIDS AIDS asymptomatic phase

11 Disease progression rate depending on the model used SIVmac251 SIVmac239 = highly pathogenic VIRAL FACTORS SIVmac239 SIVmac251 SIVmac1A11 SIVmacΔnef SIVmac1A11 = attenuated Pathogenicity rapid progression slow progression HOST FACTORS Pigtailed Macaque (Pt) Rhesus Macaque (indian) Rhesus Macaque (chinese) Cynomolgus macaque Susceptibility to AIDS rapid progression slow progression

12 Elite controler monkey model SIVagm.sab92018 rhesus macaque Pandrea et al, Plos Path, 2011

13 Reduction of lifespan in wild SIV-infected chimpanzees SIV infection with non pathogenic outcome (at least 3 natural hosts) Sooty mangabey AGM mandrill

14 SIV from natural hosts is potentially pathogenic SIVsmm9 SIVsmH4 SIVagm.ver90 SIVagm.sab92018 SIVagm.ver155 natural host macaque natural host macaque asymptomatic AIDS asymptomatic asymptomatic Fultz P et al, ARHR, 1989, Hirsch V et al, JVI, 1995; Novembre JVI, 1993, 1994; Pandrea et al, 2011

15 SIV infection: distinct models of progression/non progession Asian monkeys Macaque / SIVmac Macaque / SIVagm African monkeys Sooty mangabey / SIVsm Green monkey / SIVagm Mandrill / SIVmnd Human HIV-1 HIV-2 AIDS LTNP EC strong protection AIDS EC, HAART ALT HIC LTNP = long term no progressor HAART = highly active anti retroviral treatment EC = elite controler

16 Development of tools for the AGM/SIV model - viral load assays - cell counts (T CD4+, ) - immune assays (ICS, ) - cell differentiation & purification - microarrays MDDC Diop et al, JVI, 2000 Ploquin et al, JVI, 2004 Kornfeld et al, JCI, 2005 Jacqelin et al, Faseb J., 2007 Jacquelin et al, 2009 antigen mab crossclone reactivity m CD3 FN-18 + h CD11c S-HCL-3 + h CD14 TüK4 + h CD16 3G8 + h CD20 2H7 + h CD25 1HT44H3 + h CD40 5C3 + h CD80 L h CD83 HB15e + h CD86 FUN-1 + h CD123 7G3 + h MHC-II DR L243 + h CD1a Na1/34 - h CD1a M-T102 - h CD1a SK9 - h CD2 T11 - h CD2 Leu-5b - h CD2 MT910 - h CD3 UCTH1 - h CD3 Leu-4 - h CD14 Leu-M3 - h CD14 MΦP9 - h CD14 Mo2 - h CD19 HIB19 - h CD19 Leu-12 - h CD19 HD37 - Mortara et al, JIM, 2006

17 What is the natural host s secret of protection? SIV replicates to high levels in natural hosts. High viremia in chronic infection High viremia in acute infection High viral replication in gut High mutation rate Müller-Trutwin et al, 1996; Chakrabarti et al, 1998; Goldstein et al, 2000; Broussard et al, JVI, 2000; Gueye et al, 2004, Pandrea et al, Blood High virus replication is not sufficient to drive T CD4 depletion

18 Natural hosts do not display chronic immune activation lymph node Patient BRU unexplained lymphadenopathy Barré-Sinoussi et al, Science, 1983 HIV-1 Natural hosts: no enlarged lymph nodes CHRONIC INFECTION CD4 CD8 B FDC Ki-67 + Ki-67 + MHC-II + GC infiltrates HIV-1 progressors +++ MHC-II apoptosis Ki hyperplasia +++ virus trapping +++ cytokines (blood, tissues) HIV-1 LTNP HIV-1 HAART EC SM AGM nd / IFN-stimulated genes (ISG) Microbial translocation ++ «-» means similar to uninfected

19 When does the control of T cell activation is initiated in AGMs? SIVagm.sab92018 days weeks Blood Lymph node biopsy T CD8+ Activation acute AGM chronic 28 days p.i. T CD8+ Activation MAC acute chronic Kornfeld et al, J. Clin. Inv. 2005

20 innate immune response in natural hosts of SIV? Weak response of pdc to TLR7/9 stimulation in vitro normal response of pdc to SIV in vitro Mandl et al, Nat Med, 2008 Dunham et al, Keystone 2011 Jacquelin et al, JCI, 2008 Campillo-Gimenez, JVI, 2010

21 Acute infection in natural hosts --> Innate immune activation MAC SM AGM Acute infection: - NK proliferation - mdc maturation - pdc homing Petitjean,upublished % PDC in lymph nodes 0.30 AGM before infection after infection days p.i. Diop O et al. J. Virol Harris, L. D. et al. J. Virol

22 SIVagm-infected AGMs: strong, but only transient induction of Interferon stimulated genes (ISG) Type I ISGs (lymph nodes) AGM Jacquelin et al, J.Clin.Inv., 2009 Macaque days chronic in macaque: CCL2 CCL8 CXCL9 CXCL10 (IP10) CXCL AGM Resolution after d28p.i. (p<0.001)

23 Non-pathogenic SIVagm infection in natural hosts acute infection A short inflammation in acute phase is essential for virus and host Establishment of persistent infection Partial control of viral replication Chronic phase -- > Resolution of immune activation! Beneficial for the host, but HOW is it achieved?

24 Learning from Natural Protection against HIV/AIDS macaques HIV reservoirs & replication in the host AIDS EC natural hosts of SIV Two distinct but complementary models of protection against progression to AIDS African green monkeys Sooty Mangabey control of harmful inflammation and T cell activation

25 INSTITUT PASTEUR, Unité de Régulation des Infections Rétrovirales (F. Barré-Sinoussi) Equipe Déterminants de protection contre c le SIDA Beatrice Jacquelin Simon Jochems Anne-Sophie Liovat Gaël Petitjean Plateformes de l ANRS pour l étude des modèles simiens CEA, Fontenay-aux-Roses N. Bousquet, P. Roques, B. Vaslin Roger Le Grand Unité Epidémologie IP Marie-Anne Rey-Cuillé IHES/VRI Arndt Benecke INSTITUT PASTEUR, PARIS Animalérie GPCH C. Gommet Yves Jacob X. Montagutelli RIR A. Saez-Cirion Unité RVI O. Schwartz Yerkes, USA G. Silvestri Hôpital St Vincent de Paul Pierre Lebon NCI, Frederick J. Estes Sesame