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 #
5R01AI043222-15
Application #
8415945
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Stansell, Elizabeth H
Project Start
1998-04-01
Project End
2014-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
15
Fiscal Year
2013
Total Cost
$264,412
Indirect Cost
$103,185
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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Shan, Liang; Xing, Sifei; Yang, Hung-Chih et al. (2014) Unique characteristics of histone deacetylase inhibitors in reactivation of latent HIV-1 in Bcl-2-transduced primary resting CD4+ T cells. J Antimicrob Chemother 69:28-33
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Shan, Liang; Rabi, S Alireza; Laird, Gregory M et al. (2013) A novel PCR assay for quantification of HIV-1 RNA. J Virol 87:6521-5
Shan, Liang; Siliciano, Robert F (2013) From reactivation of latent HIV-1 to elimination of the latent reservoir: the presence of multiple barriers to viral eradication. Bioessays 35:544-52
Ho, Ya-Chi; Shan, Liang; Hosmane, Nina N et al. (2013) Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell 155:540-51
Xing, Sifei; Siliciano, Robert F (2013) Targeting HIV latency: pharmacologic strategies toward eradication. Drug Discov Today 18:541-51
Shen, Anding; Baker, Jacob J; Scott, Geoffrey L et al. (2013) Endothelial cell stimulation overcomes restriction and promotes productive and latent HIV-1 infection of resting CD4+ T cells. J Virol 87:9768-79
Durand, Christine M; Ambinder, Richard F (2013) Hematopoietic stem cell transplantation in HIV-1-infected individuals: clinical challenges and the potential for viral eradication. Curr Opin Oncol 25:180-6

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