The latent reservoir for HIV-1 in resting CD4+ T cells is a major barrier to virus eradication. There is great current interest in potential strategies for eliminating this reservoir. During the previous funding period, we have carried out mechanistic studies that have led to a reevaluation of current models of latency and have shown that mechanisms of latency are most accurately analyzed in primary cell systems rather than in transformed T cell lines. We developed an in vitro system in which primary resting CD4+ T cells carrying latent HIV-1 genomes can be generated. In this proposal, we describe the use of this system to identify and characterize small molecules capable of reactivating latent HIV-1 for use in efforts to eradicate this reservoir. We have already identified one promising hit which we will characterize mechanistically. In addition, we will use this system to explore key unanswered questions regarding the dynamics of the latent reservoir, focusing on issues that are important for eradication strategies.
The Specific Aims are (1) to determine the mechanism by which the identified hit (5-hydroxy-1,4-naphthoquinone) reactivates latent HIV-1, (2) to use the novel latency model in primary resting CD4+ T cells to screen selected small molecule libraries for other agents that reactivate latent HIV-1 without inducing global T cell activation, (3) to carry out a comparative in vitro evaluation of the efficacy of agents that reactivate latent HIV-1, and (4) to use the primary cell model to explore mechanisms involved in the maintenance of HIV-1 latency.

Public Health Relevance

HIV can persist in a silent or latent form even in patients who are treated with potent antiviral drugs. Curing HIV infection will require new ways to eliminate this latent reservoir. The studies proposed here are designed to find new drugs that can eliminate this latent reservoir.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043222-13
Application #
8013015
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Salzwedel, Karl D
Project Start
1998-04-01
Project End
2014-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
13
Fiscal Year
2011
Total Cost
$281,290
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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