Transcript Slide 1
Contribution of the immune system to HIV persistence Sharon R Lewin Director, Infectious Disease Unit, Alfred Hospital Professor, Department of Medicine, Monash University Co-head, Centre for Virology, Burnet Institute, Melbourne, Australia Towards an HIV Cure, 5th IAS Conference, Rome, 2011 Outline Establishing HIV latency – Where and how are resting T-cells infected? – Chemokines – Dendritic cells Maintaining HIV latency – Homeostatic proliferation – Inflammation Role of the adaptive immune response Relevance to strategies for cure establishing HIV latency Latent infection can be established in many T cells Bone marrow Thymus Peripheral circulation Ag M M M M Naive Multipotent progenitor cells Naïve T cells Effector/ transitional Transitional memory Central memory Central memory Latent reservoir Chun et al., Nature 1997; 387:183; Finzi et al., Science 1997; 278:1295; Brooks et al., Nat Med 2001; 7:459 ; Chomont et al., Nat Med 2009; 15: 893; Dai et al., J Virol 2009: 83(9):4528-37; Carter et al., Nat Med 2010; 16: 446; Wightman et al., J Infect Dis 2010; 202(11):1738-48 Contribution (%) to the HIV reservoir size The main reservoir is central and transitional memory T-cells 100 80 60 40 20 0 TN CD45RA CCR7 CD27 + + + TCM TTM TEM TTD + + + - + - Chomont et al., Nature Med 2009;15: 893 GI tract is enriched for latently infected cells Copies per million cells HIV DNA N=8, time on HAART with undetectable HIV RNA 2.8 – 12 years Chun et al., J Infect Dis 2008; 197:714; Yukl et al., J Infect Dis 2010; 202(10):1553-6 Most latently infected and productively infected cells are in lymphoid tissue Mmu 35389 VL=17 CSF VL<50 DNA Lymphoid tissue ++++ ++ ++ + Neg/+ Neg Reproductive tissue + Neg Other + Neg GI tract CNS RT-SHIV infection HAART =Tenofovir/emtricitabine/efavirenz RNA North et al., J Virol 2010; 84(6):2913-22 Size of HIV Reservoir correlates with activated CD8+ T cells (in Sigmoid Colon) Seth et al., Mucosal Immunology 2008:1:382-388 What is unique about these tissue sites? Ongoing replication due to – Poor penetration of drugs? – Localised sites of inflammation? Unique long-lived cells such as macrophages or DCs allowing for cell-cell transmission? Infection of resting cells? Infection of resting T-cells in vitro Unactivated resting cells Resting CD4+ T-cell In vitro Ex vivo tissue blocks chemokines Eckstein et al, Immunity 2001; 15: 671; Kreisberg et al., J Exp Med 2006; 203:865; Saleh et al., Blood 2007; 110:416; Cameron et al., Proc Natl Acad Sci 2010 epub Sept 18 Multiple chemokines can induce latent HIV infection in resting CD4+ T cells. Cameron et al., Proc Natl Acad Sci 2010; 107(39):16934-9 Chemokine receptor ligation activates cofilin and actin polymerisation CXCR4 + gp120 CCR7 + CCL19 Yoder et al Cell 2008 Cameron et al PNAS 2010 Chemokine signalling pathways PI3K PI3K SC-514 Bay 11-7082 NFB NFB JNK ERK P38 Inhibition of Erk1/2, Jnk and NF-kB eliminates integration (ALu-LTR) SP600125 PD980509 SB203580 Saleh et al., 5th IAS Conference, Rome, 2011 Infection of resting T-cells in vitro Unactivated resting cells Resting CD4+ T-cell In vitro Ex vivo tissue blocks chemokines Eckstein et al, Immunity 2001; 15: 671; Kreisberg et al., J Exp Med 2006; 203:865; Dendritic cells Saleh et al., Blood 2007; 110:416; Cameron et al., Proc Natl Acad Sci 2010 epub Sept 18 Dendritic cells facilitate latent HIV infection Evans et al., unpublished maintenance of HIV latency What is the fate of a latently infected cell? Negative regulators activation EM differentiation Homeostatic proliferation Number of latently infected cells is correlated with proliferation: role of IL-7 Chomont et al., Nat Med 2009 IL-7 increases proliferation leading to expansion of HIV DNA in vivo HIV infected subjects under suppressive HAART received IL-7 injections (ACTG5214, blind study). p=0.03 2000 800 1500 600 1000 400 500 200 0 0 Day 0 Day 28 Day 0 Day 28 Vandergreeten 6th IAS conference on HIV Pathogenesis, Treatment and Prevention, Rome, 2011 What is the fate of a latently infected cell? Negative regulators activation EM differentiation Homeostatic proliferation PD-1 hi cells are enriched for latentlly infected cells Mock a-PD-1 blocking Ab Isotype control p24 (pg/mL) Integrated HIV DNA copies per 106 CD4 T cells 600 400 200 0 Donor A Chomont et al., Nature Med 2009;15: 893 Donor B Donor C Da Fonesca et al., HIV Reservoir Workshop, Vienna, July 2010 What is the fate of a latently infected cell? Negative regulators activation IL-15 EM differentiation Homeostatic proliferation role of the adaptive immune response Inverse relationship between HIVspecific CD4+ T-cells and HIV DNA N=66; long term non progressors, no ARV Martinez et al., J Infect Dis 2001; 191:2053–63 HLA type influences size and distribution of latently infected cells HLA-B27/B57 non HLA-B27/B57 103 102 101 0.0313 TEM TTM TCM TN TEM TTM TCM p=0.0081 TN cell HIV-DNA (copies /millions cells) 104 0.0078 0.0078 0.0078 0.0469 Descours; Avettand-Fenoel Submitted Summary Latency can be established in multiple T-cell subsets High concentration of latently infected cells in tissue including GI tract and lymphoid tissue Chemokines and dendritic cells play a key role in establishing latency in resting T-cells Maintenance of latency can occur by – Homeostatic proliferation (IL-7) – Negative regulators of T-cell activation (PD1) Adaptive immune response likely important What is the fate of a latently infected cell? Anti-PD-1 Negative regulators minocycline activation vaccination EM Chemokine antagonists differentiation Auranofin IL-15 Homeostatic proliferation Anti-IL7 Acknowledgements Department of Medicine, Monash University, Melbourne – – – – – – – Paul Cameron Suha Saleh Vanessa Evans Nitasha Kumar Ajantha Solomon Georgina Sallman Fiona Wightman Westmead Millenium Research Institute, Sydney – Tony Cunningham – Andrew Harman VGTI Florida, Port St Lucie, FL – – – – Rafick Sekaly Elias Haddad Genevieve Boucher Nicolas Chomont Hopital Pitie Salpatriere, Paris – Brigitte Autran – Benjamin Descours