One of the main obstacles inhibiting HIV eradication is a population of latently infected T cells. Although small, the latent population is extremely stable and resistant to current antiretroviral therapies. Upon withdrawal of antiretroviral therapy, HIV derived from the latent reservoir is able to rekindle infection and renew progression to acquired immunodeficiency syndrome (AIDS). Consequently, viral eradication will be dependent on therapeutic strategies to specifically target and clear the latent reservoir. However in order to develop these approaches, a greater understanding of factors that control viral latency is needed. Efforts in this regard have been hampered by the lack of a suitable in vitro primary T cell model of latency. The studies proposed herein will utilize a new in vitro model to characterize multiple aspects of HIV latency including defining viral and host factors that influence viral latency, and to identify agents that may prove useful in an """"""""activation/elimination"""""""" strategy to purge latent reservoirs. To accomplish these goals, we propose the following Specific Aims: 1. To further characterize, optimize and adapt a primary cell in vitro model for HIV latency to study activation and elimination of latent virus;2. To develop a high-throughput screening method to identify additional agents that activate or inhibit activation of latently infected primary cells;3. To determine the role of viral accessory proteins in activation or formation of latent virus;4. Determine the role T regulatory cells play in viral latency. These studies will define host and viral factors influencing the latent T cell reservoir, and develop strategies to eliminate this reservoir.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI070010-05
Application #
7774382
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Salzwedel, Karl D
Project Start
2006-03-01
Project End
2011-08-07
Budget Start
2010-03-01
Budget End
2011-08-07
Support Year
5
Fiscal Year
2010
Total Cost
$364,245
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Kim, Sohn G; Lowe, Emily L; Dixit, Dhaval et al. (2015) Cocaine-mediated impact on HIV infection in humanized BLT mice. Sci Rep 5:10010
Marsden, Matthew D; Zack, Jerome A (2015) Experimental Approaches for Eliminating Latent HIV. For Immunopathol Dis Therap 6:91-99
Togher, Susan; Larange, Alexandre; Schoenberger, Stephen P et al. (2015) FoxO3 is a negative regulator of primary CD8+ T-cell expansion but not of memory formation. Immunol Cell Biol 93:120-5
Marsden, Matthew D; Zack, Jerome A (2015) Studies of retroviral infection in humanized mice. Virology 479-480:297-309
Marsden, Matthew D; Zack, Jerome A (2015) Double trouble: HIV latency and CTL escape. Cell Host Microbe 17:141-2
Sanchez, David Jesse; Miranda Jr, Daniel; Marsden, Matthew D et al. (2015) Disruption of Type I Interferon Induction by HIV Infection of T Cells. PLoS One 10:e0137951
Marsden, Matthew D; Zack, Jerome A (2014) Neutralizing the HIV reservoir. Cell 158:971-972
Marsden, Matthew D; Zack, Jerome A (2013) HIV/AIDS eradication. Bioorg Med Chem Lett 23:4003-10
Zack, Jerome A; Kim, Sohn G; Vatakis, Dimitrios N (2013) HIV restriction in quiescent CD4? T cells. Retrovirology 10:37
Kim, Sohn G; Jung, James B; Dixit, Dhaval et al. (2013) Cocaine exposure enhances permissiveness of quiescent T cells to HIV infection. J Leukoc Biol 94:835-43

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