Identifying where HIV persists in HIV-infected patients on suppressive therapy is a critically important step towards HIV eradication. For practical reasons, the study of viral reservoirs has largely focused on components of peripheral blood. Recent findings, however, show that tissue sites harbor a substantial proportion of infected cells. The overall goal of this Project is to identify the source, dynamics, and nature of the reservoir producing persistent HIV infection in patients on suppressive therapy in a range of tissue sites. The research team will determine the nature of HIV persistence/latency in T-cell subsets (naive, memory, central memory and effector/transitional memory) and hematopoietic progenitor cells from the small bowel, large bowel, lymph nodes, and bone marrow of patients on long-term therapy (>7 years) who initiated therapy during acute and chronic infection. We will also investigate HIV in rare circulating cells (which will be obtained from leukapheresis). Unique and innovative techniques will be used to (1) analyze the genetic make-up of HIV populations in the cell subsets, (2) quantify the levels of intracellular HIV DNA and unspliced RNA/spliced RNA and, using a novel nucleic acid chemistry for primer-probe design, measure short abortive HIV transcripts, (3) determine the replication competence of the HIV remaining in different cellular subsets, (4) reveal host cell factors that determine which cells may harbor or resist replicating and/or latent HIV and (5) examine the effect of collagen deposition and fibrosis on the size and distribution of the reservoirs. We will also support complementary work being done in tissue-based macrophages (Project 4). In addition to understanding how HIV is subdivided among different cells and tissues, the proposed study will provide a systematic survey of how lymphoid cell host factors and changes in lymph node tissue structure support HIV latency and help determine the magnitude and nature of the viral reservoirs. We believe that this study will provide an unprecedented quantitative assessment of total body stores of virus and that our findings will guide treatment interventions that can reduce and eradicate persistent HIV reservoirs.
Current effective HIV therapy is not curative. Residual HIV persists in the cells of treated patients, but its precise cellular source is unknown. This project will apply novel technologies that have never before been used in parallel to study an unprecedented number of diverse tissue-derived cells from treated HIV patients. These studies will help to identify the source of persistent HIV, to inform HIV treatment, and to guide efforts toward HIV eradication.
|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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