A major barrier to HIV eradication is the existence of a small pool of long-lived latently-infected, resting memory CD4[+] T cells carrying an integrated form of the viral genome. Memory T cells encompass a variety of cell subsets all endowed with specific survival and differentiation properties. We have recently demonstrated that the privileged cell type where HIV establishes its resen/oir is the central memory T cell (T{CM}) and its immediate progeny, the transitional memory T cell (T{TM})- IL-7 is one of the cytokines that is responsible for sustaining low levels of proliferation in T{CM} and T{TM}. Harnessing IL-7 interactions with its receptor on TCM could provide a strategy to prevent the survival and proliferation of these cells, and to prevent the persistence of the HIV reservoir. Another cytokine known to play a major role in memory T cell survival is IL-15. We have recently demonstrated that IL-15 engagement with its receptor on resting CD4[+] T{CM} that harbor latent virus will induce their differentiation into short-lived effector memory T cells (T{EM}) that can proliferate and produce virus. We propose to exploit this capacity of IL-15 so that the pool of resting, infected T{CM} cells can be depleted in vitro and in vivo. We will first determine the relative impact of IL-7 and IL-15 on HIV persistence in vivo and in vitro by measuring the contribution of these cytokines to the maintenance of the pool of latently infected cells in blood and tissues obtained from subjects receiving suppressive ART and by evaluating their capacity to induce viral reactivation (Specific Aim 1). We will then test the hypothesis that blocking the IL-7 pathway or, conversely, administrating IL-15 to optimally-treated macaquess could be used as strategies to deplete the latent viral reservoir (Specific Aim 2). Our proposed interventions target the major cellular source of persistent virus during treatment, and although they may not work alone in eradicating HIV, they could complement other interventions by transiently reversing the host factors that are critical in maintaining latently infected cells.

Public Health Relevance

Eradication of HIV has been the focus of several clinical interventions that unfortunately have failed to reach their goal. Most of these strategies have relied on the use of complex antiviral regimens to test the hypothesis that eradication of HIV can be achieved by inhibiting the residual viral replication in CD4[+] T cells or in other compartments. In this project, we will focus on those host factors that contribute to maintanece of latency and which could be reversed using targeted therapeutic strategies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-JBS-A (M1))
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University of California San Francisco
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Tjiam, M Christian; Morshidi, Mazmah A; Sariputra, Lucy et al. (2017) Association of HIV-1 Gag-Specific IgG Antibodies With Natural Control of HIV-1 Infection in Individuals Not Carrying HLA-B*57: 01 Is Only Observed in Viremic Controllers. J Acquir Immune Defic Syndr 76:e90-e92
Martin, Alyssa R; Pollack, Ross A; Capoferri, Adam et al. (2017) Rapamycin-mediated mTOR inhibition uncouples HIV-1 latency reversal from cytokine-associated toxicity. J Clin Invest 127:651-656
Power, Jennifer; Fileborn, Bianca; Dowsett, Gary W et al. (2017) HIV cure research: print and online media reporting in Australia. J Virus Erad 3:229-235
Winckelmann, Anni; Barton, Kirston; Hiener, Bonnie et al. (2017) Romidepsin-induced HIV-1 viremia during effective ART contains identical viral sequences with few deleterious mutations. AIDS :
Mota, Talia M; Rasmussen, Thomas A; Rhodes, Ajantha et al. (2017) No adverse safety or virological changes 2 years following vorinostat in HIV-infected individuals on antiretroviral therapy. AIDS 31:1137-1141
Rasmussen, Thomas A; Anderson, Jenny L; Wightman, Fiona et al. (2017) Cancer therapies in HIV cure research. Curr Opin HIV AIDS 12:96-104
Kaiser, Philipp; Joshi, Sunil K; Kim, Peggy et al. (2017) Assays for precise quantification of total (including short) and elongated HIV-1 transcripts. J Virol Methods 242:1-8
Symons, Jori; Chopra, Abha; Malatinkova, Eva et al. (2017) HIV integration sites in latently infected cell lines: evidence of ongoing replication. Retrovirology 14:2
Tauriainen, Johanna; Scharf, Lydia; Frederiksen, Juliet et al. (2017) Perturbed CD8+ T cell TIGIT/CD226/PVR axis despite early initiation of antiretroviral treatment in HIV infected individuals. Sci Rep 7:40354
Seang, Sophie; Somasunderam, Anoma; Nigalye, Maitreyee et al. (2017) Circulating LOXL2 Levels Reflect Severity of Intestinal Fibrosis and GALT CD4+ T Lymphocyte Depletion in Treated HIV Infection. Pathog Immun 2:239-252

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