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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA030156-04
Application #
8433516
Study Section
Special Emphasis Panel (ZDA1-SXC-E (14))
Program Officer
Satterlee, John S
Project Start
2010-07-15
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2013
Total Cost
$580,859
Indirect Cost
$126,460
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Garrido, Carolina; Margolis, David M (2015) Translational challenges in targeting latent HIV infection and the CNS reservoir problem. J Neurovirol 21:222-6
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
Archin, Nancie M; Margolis, David M (2014) Emerging strategies to deplete the HIV reservoir. Curr Opin Infect Dis 27:29-35
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
Barton, Kirston; Margolis, David (2013) Selective targeting of the repressive transcription factors YY1 and cMyc to disrupt quiescent human immunodeficiency viruses. AIDS Res Hum Retroviruses 29:289-98
Margolis, David M; Hazuda, Daria J (2013) Combined approaches for HIV cure. Curr Opin HIV AIDS 8:230-5
Margolis, David M (2011) Eradication therapies for HIV Infection: time to begin again. AIDS Res Hum Retroviruses 27:347-53
Margolis, David M (2011) Histone deacetylase inhibitors and HIV latency. Curr Opin HIV AIDS 6:25-9
Choudhary, Shailesh K; Margolis, David M (2011) Curing HIV: Pharmacologic approaches to target HIV-1 latency. Annu Rev Pharmacol Toxicol 51:397-418

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