Current antiretroviral therapy can nearly eliminate viremia and most active HIV replication. The potency of future therapies is likely to increase. However, a subpopulation of HIV-infected lymphocytes avoids viral or immune cytolysis and returns to the resting state. This reservoir will persist without new therapeutic approaches. We have defined a mechanism that may establish or maintain viral quiescence in T cells. We have shown that host factors form a complex at the HIV long terminal repeat (LTR) promoter, inhibiting HIV gene expression. LSF recruits YY1 to the LTR. YYI in turn recruits histone deacetylase 1 (HDACI), a chromatin remodeling enzyme that inhibits transcription. Significantly, we have validated the biological relevance of these findings in resting CD4+ cells obtained from HIV+ donors. Using polyamides, synthetic cell-permeable small molecules that bind DNA in a sequence-specific manner and inhibit DNA- protein interactions, we have directly demonstrated inhibition of LSF binding at the LTR and increased LTR expression in T cells. Exposing resting CD4+ cells obtained from aviremic HIV-infected donors to specific polyamides results in HIV outgrowth. To confirm and extend our studies, we will test these hypotheses:
Specific Aim I : To elucidate the regulation of the LSF/YYI/HDACI LTR repressor complex: phosphorylation and acetylation regulate repressor complex assembly.
Specific Aim II : To study the counter-regulation of LTR expression by chromatin-modifying enzymes: HATS and HDACI compete, affecting LTR architecture, and viral and host transcription factor activity.
Specific Aim III : To measure HIV expression after disruption of repressor function in primary cells: Both a novel tool and a potential therapeutic, polyamides allow the study of factors that restrict the expression of HIV within resting CD4+ cells obtained from HIV+ donors. Studies of downregulation of HIV gene expression and the role of host factors in the quiescent, aviremic HIV infection may give insight into general mechanisms of transcriptional regulation, T cell and HIV biology, and lead to rational therapies directed at the persistent reservoir of HIV infection within resting CD4+ T cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI045297-05
Application #
6553923
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (11))
Program Officer
Young, Janet M
Project Start
1999-07-01
Project End
2007-05-31
Budget Start
2002-08-01
Budget End
2003-05-31
Support Year
5
Fiscal Year
2002
Total Cost
$315,900
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Anderson, Jeffrey A; Archin, Nancie M; Ince, William et al. (2011) Clonal sequences recovered from plasma from patients with residual HIV-1 viremia and on intensified antiretroviral therapy are identical to replicating viral RNAs recovered from circulating resting CD4+ T cells. J Virol 85:5220-3
Archin, Nancie M; Cheema, Manzoor; Parker, Daniel et al. (2010) Antiretroviral intensification and valproic acid lack sustained effect on residual HIV-1 viremia or resting CD4+ cell infection. PLoS One 5:e9390
Keedy, Kara S; Margolis, David M (2010) Therapy for persistent HIV. Trends Pharmacol Sci 31:206-11
Bowman, Mary-Catherine; Archin, Nancie M; Margolis, David M (2009) Pharmaceutical approaches to eradication of persistent HIV infection. Expert Rev Mol Med 11:e6
Keedy, Kara S; Archin, Nancie M; Gates, Adam T et al. (2009) A limited group of class I histone deacetylases acts to repress human immunodeficiency virus type 1 expression. J Virol 83:4749-56
Bowman, Mary-Catherine; Ballard, T Eric; Ackerson, Christopher J et al. (2008) Inhibition of HIV fusion with multivalent gold nanoparticles. J Am Chem Soc 130:6896-7
Klichko, Vladimir; Archin, Nancy; Kaur, Rupinderjeet et al. (2006) Hexamethylbisacetamide remodels the human immunodeficiency virus type 1 (HIV-1) promoter and induces Tat-independent HIV-1 expression but blunts cell activation. J Virol 80:4570-9
Lehrman, Ginger; Hogue, Ian B; Palmer, Sarah et al. (2005) Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet 366:549-55
Ylisastigui, Loyda; Kaur, Rupinderjeet; Johnson, Holly et al. (2005) Mitogen-activated protein kinases regulate LSF occupancy at the human immunodeficiency virus type 1 promoter. J Virol 79:5952-62
Ylisastigui, Loyda; Archin, Nancie M; Lehrman, Ginger et al. (2004) Coaxing HIV-1 from resting CD4 T cells: histone deacetylase inhibition allows latent viral expression. AIDS 18:1101-8

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