The integration of retroviral genomes into host chromatin allows HIV to persist within infected cells. The difficulties of lifelong therapy make it imperative to understand the mechanisms of persistent HIV infection, to devise strategies to overcome latent HIV infection. Histone modifying enzymes play a critical role in proviral latency, and histone deacetylase (HDAC) inhibitors induce HIV promoter and viral expression. Drugs of abuse, most notably cocaine, can alter cellular function via epigenetic modification. The durable, epigenetic effect of such environmental influences on memory T cells and persistent HIV infection is unexplored. A more complete understanding of how epigenetics modulate HIV proviral quiescence, and whether latent infection is altered by exposure to cocaine is needed. To achieve this we will comprehensively evaluate the following hypotheses using transformed and primary cell models of latency, and latently infected cells obtained from patients, including patients with a history of cocaine exposure.
Specific Aim I : Selected HDACs are specifically recruited to act at the HIV promoter, and targeted HDAC inhibition induces the expression of quiescent proviral HIV: Cofactor complexes recruit HDACs 1, 2, and 3 to act on the HIV LTR, where HDAC isoform occupancy is autoregulated. Blockade of the function of selected HDACs can induce latent proviral expression in model systems, and allow viral recovery from the resting CD4+ T cells of HIV-infected, ART-treated patients.
Specific Aim II : Histone deacetylation is an early step in the establishment of restrictive chromatin structures on the silenced LTR: An extensive series of chromatin modifications following histone deacetylation, including histone methylation, results in transition from the """"""""inducible"""""""" to the """"""""locked"""""""" state, decreasing responsiveness of the HIV promoter to single inductive signals.
Specific Aim III : Cocaine use will alter the population of latently infected cells, reducing their response to inductive signals: By inducing histone acetylation in resting CD4+ T cells, cocaine exposure will reduce the number of latently infected cells in the """"""""inducible state"""""""" responsive to HDAC inhibitors. Detailed studies of the epigenetics and regulation of proviral quiescence in HIV-infected patients, including the effects of drugs of abuse on latent HIV infection, will enhance our understanding of persistent HIV infection. These studies will guide the development of therapeutic approaches to disrupt persistent proviral infection, and insure that such approaches are applicable to broad populations of patients.
Highly active antiretroviral therapy (ART) has lead to a significant decrease in the morbidity and mortality of HIV-infected individuals, but eradication of virus from HIV-infected individuals remains a distant prospect due largely to the ability of HIV to establish latency in resting CD4+ T-lymphocytes. To overcome HIV latency in a broad population of infected individuals, it is also important to assess the effect of environmental exposures, such as those to drugs of abuse, on persistent HIV infection. Therefore a more detailed understanding is needed of the epigenetic mechanisms behind persistent infection.
|Burch, Brandon D; Garrido, Carolina; Margolis, David M (2017) Detection of human immunodeficiency virus RNAs in living cells using Spinach RNA aptamers. Virus Res 228:141-146|
|Garrido, Carolina; Margolis, David M (2015) Translational challenges in targeting latent HIV infection and the CNS reservoir problem. J Neurovirol 21:222-6|
|Crooks, Amanda M; Bateson, Rosalie; Cope, Anna B et al. (2015) Precise Quantitation of the Latent HIV-1 Reservoir: Implications for Eradication Strategies. J Infect Dis 212:1361-5|
|Archin, Nancie M; Sung, Julia Marsh; Garrido, Carolina et al. (2014) Eradicating HIV-1 infection: seeking to clear a persistent pathogen. Nat Rev Microbiol 12:750-64|
|Barton, Kirston M; Archin, Nancie M; Keedy, Kara S et al. (2014) Selective HDAC inhibition for the disruption of latent HIV-1 infection. PLoS One 9:e102684|
|Salgado, Maria; Swanson, Michael D; Pohlmeyer, Christopher W et al. (2014) HLA-B*57 elite suppressor and chronic progressor HIV-1 isolates replicate vigorously and cause CD4+ T cell depletion in humanized BLT mice. J Virol 88:3340-52|
|Archin, Nancie M; Margolis, David M (2014) Emerging strategies to deplete the HIV reservoir. Curr Opin Infect Dis 27:29-35|
|Manson McManamy, Mary E; Hakre, Shweta; Verdin, Eric M et al. (2014) Therapy for latent HIV-1 infection: the role of histone deacetylase inhibitors. Antivir Chem Chemother 23:145-9|
|Soriano-Sarabia, Natalia; Bateson, Rosalie E; Dahl, Noelle P et al. (2014) Quantitation of replication-competent HIV-1 in populations of resting CD4+ T cells. J Virol 88:14070-7|
|Honeycutt, Jenna B; Wahl, Angela; Archin, Nancie et al. (2013) HIV-1 infection, response to treatment and establishment of viral latency in a novel humanized T cell-only mouse (TOM) model. Retrovirology 10:121|
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