Precisely characterizing HIV rebound when antiretroviral therapy (ART) is stopped can offer valuable insights into HIV reservoirs including: ? What biological quantities can predict viral rebound dynamics (timing, set-point, slope), ? How HIV populates blood cells and anatomic compartments, and ? What immune mechanisms are associated with HIV population size and activity, rebound characteristics, and viral population of circulating CD4+ T cells and tissues. A sticky clinical research dilemma is that clinical compromise can occur when ART is stopped. To overcome these dilemmas, the proposed Revealing Reservoirs during Rebound (R3) will: ? Analyze currently available clinical, virological and immunological data from 504 well-characterized participants who started ART during acute and early infection, achieved sustained viral suppression, and then interrupted this therapy under monitored studies (Early Treatment Research Project); ? Generate new virologic and immunologic data from blood samples collected from 60 participants in the Zurich Primary Infection cohort and 30 participants in the AIDS Clinical Trials Group study ?Identification of Biomarkers to Predict Time to Plasma HIV RNA Rebound and Post-Treatment Viral Control during an Intensively Monitored Antiretroviral Pause (IMAP)? (A5345) (Early Treatment Research Project); ? Evaluate 20 altruistic HIV-infected people on ART who are terminally-ill and who have voluntarily decided to stop their ART before they die, and who will provide us their blood before and after they stop ART, then their bodies after they die (Late Treatment Research Project); ? These large and diverse sets of data, which will require the development of new analytical methods to answer important questions relevant to the HIV cure agenda (Quantitative Methods Research Project). These three Research Projects will be supported by three Cores. ? The Administrative Core will ensure effective and efficient management of the program; ? The Clinical and Pathology Core will ensure appropriate collection and management of R3 specimens; ? The Quality Assurance and Data Core will ensure quality of data that are collected, generated and analyzed across the program. Altogether, the R3 will address these open questions to provide tangible metrics to guide the development of HIV cure strategies and inform the use of biomarkers to ascertain whether or not a cure effort has the intended effect without interrupting ART.

Public Health Relevance

This program will investigate HIV-infected study volunteers who started HIV therapy during early infection and some who started during chronic infection; all of whom who interrupted this therapy. Data collected and generated by this program will be analyzed using state-of-the-art and new methods. Results of these analyses will guide the development of strategies targeting HIV reservoirs throughout the body and inform the use of biomarkers to ascertain whether or not a cure effort has the intended effect- ultimately without the need of interrupting therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI131385-03
Application #
9752454
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Refsland, Eric William
Project Start
2017-08-01
Project End
2022-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Hill, Alison L; Rosenbloom, Daniel I S; Nowak, Martin A et al. (2018) Insight into treatment of HIV infection from viral dynamics models. Immunol Rev 285:9-25
Gianella, Sara; Sonya Haw, J; Blumenthal, Jill et al. (2018) The Importance of Human Immunodeficiency Virus Research for Transgender and Gender-Nonbinary Individuals. Clin Infect Dis 66:1460-1466
Dubé, Karine; Luter, Stuart; Lesnar, Breanne et al. (2018) Use of 'eradication' in HIV cure-related research: a public health debate. BMC Public Health 18:245
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Burlacu, Ruxandra; Umlauf, Anya; Luca, Anca et al. (2018) Sex-based differences in neurocognitive functioning in HIV-infected young adults. AIDS 32:217-225
Hill, Alison L (2018) Mathematical Models of HIV Latency. Curr Top Microbiol Immunol 417:131-156
Hill, Alison L (2018) Modeling HIV persistence and cure studies. Curr Opin HIV AIDS 13:428-434
Letendre, Scott; Bharti, Ajay; Perez-Valero, Ignacio et al. (2018) Higher Anti-Cytomegalovirus Immunoglobulin G Concentrations Are Associated With Worse Neurocognitive Performance During Suppressive Antiretroviral Therapy. Clin Infect Dis 67:770-777
Lin, Timothy C; Gianella, Sara; Tenenbaum, Tara et al. (2018) A Simple Symptom Score for Acute Human Immunodeficiency Virus Infection in a San Diego Community-Based Screening Program. Clin Infect Dis 67:105-111

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