1. Rémi Cheynier Victor Appay Anne Hosmalin Gianfranco Pancino Vincent Vieillard Brigitte Autran Françoise Brun-Vezinet Charlotte Charpentier Diane Descamps Florence Damond Sophie Matheron Antoine Benard Rodolphe Thiebaut Geneviève Chêne HIV-2: ANRS Immuno-Virological Network + F Simon, F Clavel & M Benkirane & S Benichou

2. A model of attenuated HIV infection in humans HIV-2 Limited chronic immune activation Good immune reconstitution Immune preservation Low viral replication Low viral load Good immune control Controlled viral replication Virtuous circle Controlled viral replication Restriction factors Vpx like SIV, nef? Molecular characteristics of HIV-2? Low Type I IFN and IRG signature like AGM? Other Inflammatory cytokines? Renewal capacity Low senescence? NK cells CD4 and CD8 responses: like controllers? Progressors among HIV-2 infected patients Dendritic cells? Monocytes? Distribution of cellular reservoir? Initial viral spread Hypothesis: preservation of the host immune resources due to reduced viral replication and limited immune activation enabling stable capacity to control the viral infection

3. A model of attenuated HIV infection in humans HIV-1 Uncontrolled viral replication Chronic immune activation Viral replication Poor immune reconstitution Immune exhaustion Poor immune control High viral load HIV-2 Limited chronic immune activation Good immune reconstitution Immune preservation Low viral replication Low viral load Good immune control Uncontrolled viral replication Controlled viral replication Vicious circleVirtuous circle Controlled viral replication Initial viral spread Restriction factors Vpx like SIV, nef? Molecular characteristics? Low Type I IFN and IRG signature like AGM? Other Inflammatory cytokines? Renewal capacity Low senescence? NK cells CD4 and CD8 responses: like controllers? Dendritic cells? Monocytes? Cellular reservoir? Initial viral spread

4. Study Population: ANRS CO5 HIV-2 cohort  20 progressors starting ART  B, C events  CD4<500cells/µl  CD4>500/µl with loss of >50C/y  Immunological study at baseline and 1 year  Reservoir study at baseline  Pilot therapeutic trial with RAL containing regimen  20 non progressors  Immunological study  Reservoir study  10 relatives, HIV negative healthy volunteers  Immunological study

5. Immune correlates of disease protection in HIV-2 infection? (AO ANRS 2-2010) Innate and adaptative immunity in the control of HIV-2 infection?  Renewal capacity in lymphoid compartments R Cheynier Preservation of immune resources (e.g. lymphoid progenitors, RTEs, thymic function); Higher thymic function and lower CD4 loss? Cytokine production (IFN-I, inflammatory cytokines, Th1 … )  T-cell activation and differentiation -Immunological senescence V Appay  Innate immunity Functional study of dendritic cells (cDC, pDC, BDCA3+) A Hosmalin Phenotype and functions of NK cells V Vieillard,  Anti-viral activity in CD8 compartments G Pancino

6. HIV-2 Reservoir? (AO ANRS 1-2011)  Question  Is there a particular distribution of the HIV-2 reservoir in the CD4 T cells with a protection of the T CM cells and a larger reservoir size in the T TM cells as observed in Elite Controllers HIV-1 infected patients?  Is the HIV-2 viral replication limited in all suceptible cells, with comparable amount of proviral DNA in T CM and T TM CD4? linked to the molecular characteristics of the viral replication?

7. HIV2 Reservoir □ Quantification of HIV-2 reservoir Plasma HIV-2 RNA (detection threshold at ≈4c/ml) Intracellular HIV-2 DNA (total, integrated, 2LTR) in different cell compartments: PBMC, macrophages, naïve, T CM, T TM et T EM Detection of infectious virus by co-culture and quantification of HIV-2 RNA in culture supernatants □ Phylogenetic characterization of viruses In the different lymphocyte subsets As compared to plasma virus and to virus detected in total PBMCs Restriction factors - host and virus sequences (SAMHD1-Vpx ) □ Phenotypic and genotypic analyses of nef gene S Benichou

8. R. THIEBAUT, R. ANTOINE, C. CHARPENTIER, F. DAMOND, A. TAIEB, G. CHENE, G. COLLIN, S. MATHERON, D. DESCAMPS, F. BRUN-VÉZINET. INSERM U897, Université Segalen, ISPED, Bordeaux, France;Laboratoire de Virologie, APHP, Bichat-Cl Bernard, Université P7, Paris, France; Service de Maladies Infectieuses et Tropicales, APHP, Bichat-Cl Bernard, Paris, France. Association of sCD14 and Inflammatory Markers with HIV-2 Disease Progression, ANRS CO5 (ICAAC 2011)