Latent or persistent reservoirs of HIV infection are thought to give rise to renewed viral replication following cessation of HAART. It is felt that the presence of these reservoirs dictates that patients must remain on antiviral therapy for life. Thus any increased understanding of the biology of latent reservoirs would be quite important. In addition, devising ways to purge latent or persistent reservoirs may hold promise for the treatment of HIV disease. Our laboratory has earlier proposed an """"""""activation/elimination"""""""" approach whereby latently infected cells are activated to express virus, and subsequently targeted for destruction by specific anti-HIV immunotoxins. We now have at our disposal several novel synthetic protein kinase (PKC) activators that appear to be quite active in their ability to induce the expression of latent HIV. We are also exploring novel nanoparticle delivery vehicles, which can specifically target activating agents to CD4-bearing cells. In addition, we have found reproducible latent reservoirs in the thymus, blood and spleens of an improved humanized mouse model, the BLT mouse. We will couple these systems to gain a greater understanding of the biology of latent HIV infection. We will also use these systems to develop a strategy to activate latent HIV, in both in vitro and in vivo systems. We will accomplish this through the following Specific Aims: 1) Define and characterize the various viral reservoirs in the BLT mouse model;2) Characterize and optimize novel PKC activators coupled with new delivery methods for stimulating viral reservoirs in vitro and ex vivo;3) Explore the use of novel PKC activators and delivery methods to stimulate latent HIV in BLT mice on HAART. We hope that these studies will provide proof-of-concept that specific activation of viral reservoirs can be accomplished in vivo, and that valuable pre-clinical data regarding this approach will be obtained. If successful, these studies could pave the way for future clinical trials of this type of approach to decrease or eliminate persistent viral reservoirs.

Public Health Relevance

Latent or persistent reservoirs of HIV-1 may be the chief hurdle to eradication of infection, as they harbor integrated virus that can rekindle active infection if therapy is discontinued. This proposal aims to develop methods to attack latent reservoirs by an activation strategy. Knowledge gained could point the way towards improved clinical management of AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI070010-06A1
Application #
8209588
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Salzwedel, Karl D
Project Start
2006-03-01
Project End
2015-07-31
Budget Start
2011-08-08
Budget End
2012-07-31
Support Year
6
Fiscal Year
2011
Total Cost
$385,000
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
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 (2015) Double trouble: HIV latency and CTL escape. Cell Host Microbe 17:141-2
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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