1. Natural and induced control of HIV infection: differences and similarities VISCONTI Study Asier Sáez-Cirión, PhD Unité de Régulation des Infections Rétrovirales Institut Pasteur, Paris, France

2. At least 5 years of infection, naïve of cARV, maintain 5 last viral loads < 400 copies Buffassa et al, PLoS One 2011 HIV controllers (HIC): infected individuals spontaneously controlling HIV-1 infection Post-treatment controllers (PTC): infected individuals controlling HIV-1 infection after interruption of cART 14 patients Months on cART : 36.5 (12-92) Months post-cART: 89 (48-115) Therapy started within 10 weeks following Primary Infection (median 39 days p.i.) Saez-Cirion et al PLoS Path 2013 HIV controllers and Post-treatment controllers different ways for a similar outcome

3. Post-treatment controllers had a tougher primary infection than HIV controllers pre-HICpre-PTCPRIMO Non controllers CD4+ T cells counts at PHI (cells/µl) 200 400 600 800 1000 1200 pre-HICpre-PTCPRIMO Non controllers Plasma RNA Viral load at PHI (log copies/ml) 0 2 4 6 8 p=0.02 p=0.002 p=0.88 p=0.68 Saez-Cirion et al PLoS Path 2013

4. Post-treatment controllers do not have a favorable MHC background FranceHIC Allele frequency (%) 0 10 20 30 40 50 60 PTC B27 B57 B35 B07 Saez-Cirion et al PLoS Path 2013

5. Saez-Cirion et al, JI 2009 R=0.836, p<0.00001 log p24 decrease (CD4 vs CD4:CD8 1:1) 012345 IFN  SFC total/10 6 PBMC 0 2000 4000 6000 8000 10000 12000 14000 16000 Days post infection 3710 p24 (ng/ml) 10 10 0 1 2 3 4 CD4 T cells CD4:CD8 1:1 Saez-Cirion et al, PNAS 2007; Nature Protocols 2010 Efficient T cell responses are associated with natural control Greater and faster upregultaion of cytotoxic mediators Migueles, et al. Immunity 2008; Hersperger, et al. PLoS Pathogens 2010

6. Lecuroux et al PLoS One, 2013 Strong CD8- T cell capacity to suppress HIV-1 is usually absent in PHI Median drop of -0.94 log HIV-1 RNA copies/ml within 7 days 50 patients in PHI (median 35 days p.i.)

7. Post-treatment controllers have weak HIV-specific CD8+ T cell responses VIRHAARTHIC log p24 decrease (CD4 vs CD4:CD8) 0 1 2 3 4 <0.001 VIRHAARTHIC IFN  (SFC/10 6 PBMC) 0 2000 4000 6000 8000 10000 12000 IFN  ELISPOT <0.001 <0.01 PTC <0.001 PTC Saez-Cirion et al PLoS Path 2013 HIV suppression

8. Post-treatment controllers have weak levels of T cell activation CD38+HLA-DR+CD38+HLA-DR+ % of CD3+ CD8+ cells 0 10 20 30 40 50 60 70 HAART HIC PTC p < 0.001 Saez-Cirion et al PLoS Path 2013

9. Both HIC and PTC are infected with replication competent HIV-1 days of culture 051015202530 p24 in culure supernatants p24 (ng/ml) 0.01 0.1 1 10 100 1000 Viral replication in CD4+ T cells from healthy donor

10. 3538 patients included in the FHDH within 6 months of primary infection 1997-2011 756 patients treated within 6 months and at least for a year 74 patients with a viral load below <50 RNA copies/ml who stop = 2% of PHI patients Goujard et al Antivir Ther 2012: N=164 patients, 8.5% VL<50 at M24 Hocqueloux et al AIDS 2010: N=32 patients, 15.6% VL<50 at M24 Probability to keep controlling infection at 24M (loss of control: 2VL>50 RNA copies/ml or 1VL>50 RNA copies/ml +cART) : 15.7% [6.5-28.5] Months post-treatment interruption Probability to loss control Saez-Cirion et al PLoS Path 2013 A long-term treatment initiated during primary infection seems to increase the chances to control viremia

11. HIC vs PTC HIV controllers (HIC) Asymptomatic primary infection: low viral loads and high CD4 T cell counts in PHI 80% HIC carry one protective HLA-class I allele Generally strong HIV-specific T cell responses with strong capacity to eliminate infected cells Abnormal high levels of T cell activation Estimated frequency: 0.5% of HIV infected patients Post-Treatment Controllers (PTC) Symptomatic primary infection: high viral loads and low CD4 T cell counts in PHI 57% PTC carry one HLA-class I allele associated with high viral loads Generally very weak HIV-specific T cell responses with poor capacity to eliminate infected cells Low levels of T cell activation Estimated frequency: 5-15% of HIV infected patients interrupting a >12 months-length treatment initiated in primary infection

12. Exploring other mechanisms that have been proposed to contribute to natural control of infection… Weak cell susceptibility to HIV-1 infection, contributing to limit the reservoirs in HIC Innate immunity, NK cells, may contribute to limit replication in acute infection Enhanced ADCC activity may contribute to control of infection, in particular in HLA-B*57neg HIC

13. Acknowledgements Institut Pasteur Régulation des Infections Rétrovirales Gianfranco Pancino Daniel Scott-Algara Françoise Barré-Sinoussi Annie David Pierre Versmisse Faculté de Médecine Paris Sud INSERM U1012 Alain Venet Olivier Lambotte Jean-François Delfraissy Cécile Goujard Isabelle Girault Camille Lecuroux INSERM U1018 Laurence Meyer Faroudy Boufassa CHU Necker Enfants Malades Laboratoire de Virologie Christine Rouzioux Véronique Avettand-Fenoel Adeline Mélard CHR Orléans La Source Service Maladies Infectieuses Laurent Hocqueloux Thierry Prazuck CHU Hôtel-Dieu Unité Immuno-Infectiologie Jean-Paul Viard ANRS CO18 “HIV controllers” ANRS CO15 “ALT” Patients and clinicians who participate in the study CHU Pitié-Salpetriere INSERM UMR-S 945 Brigitte Autran Charline Bacchus Benjamin Descours Assia Samri Ioannis Theodorou Julien Guergnon ANRS CO6 “PRIMO” INSERM UPMC U943 Dominique Costagliola Valérie Portard FHDH “French Hospital Database on HIV”