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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-JBS-A)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
San Francisco
United States
Zip Code
Delagrèverie, Héloïse M; Delaugerre, Constance; Lewin, Sharon R et al. (2016) Ongoing Clinical Trials of Human Immunodeficiency Virus Latency-Reversing and Immunomodulatory Agents. Open Forum Infect Dis 3:ofw189
Hansen, Erik C; Ransom, Monica; Hesselberth, Jay R et al. (2016) Diverse fates of uracilated HIV-1 DNA during infection of myeloid lineage cells. Elife 5:
Barton, Kirston; Hiener, Bonnie; Winckelmann, Anni et al. (2016) Broad activation of latent HIV-1 in vivo. Nat Commun 7:12731
Murray, Alexandra J; Kwon, Kyungyoon J; Farber, Donna L et al. (2016) The Latent Reservoir for HIV-1: How Immunologic Memory and Clonal Expansion Contribute to HIV-1 Persistence. J Immunol 197:407-17
Crowell, Trevor A; Fletcher, James Lk; Sereti, Irini et al. (2016) Initiation of antiretroviral therapy before detection of colonic infiltration by HIV reduces viral reservoirs, inflammation and immune activation. J Int AIDS Soc 19:21163
Yong, Yean K; Shankar, Esaki M; Solomon, Ajantha et al. (2016) Polymorphisms in the CD14 and TLR4 genes independently predict CD4+ T-cell recovery in HIV-infected individuals on antiretroviral therapy. AIDS 30:2159-68
Siliciano, Janet D; Siliciano, Robert F (2016) Recent developments in the effort to cure HIV infection: going beyond N = 1. J Clin Invest 126:409-14
Phillips, Andrew N; Cambiano, Valentina; Revill, Paul et al. (2016) Identifying Key Drivers of the Impact of an HIV Cure Intervention in Sub-Saharan Africa. J Infect Dis 214:73-9
Sattentau, Quentin J; Stevenson, Mario (2016) Macrophages and HIV-1: An Unhealthy Constellation. Cell Host Microbe 19:304-10
Massanella, Marta; Fromentin, Rémi; Chomont, Nicolas (2016) Residual inflammation and viral reservoirs: alliance against an HIV cure. Curr Opin HIV AIDS 11:234-41

Showing the most recent 10 out of 133 publications