HIV latency: Selective Inhibitors of Histone Deacetylase (HDAC) Isoforms - In order to eliminate infection in HIV-positive patients, latent viral reservoirs must be purged to render infected cells susceptible to antivirals. HDAC3 appears to be the primary HDAC responsible for HIV latency in model cell lines, and a specific inhibitor of HDAC3 should overcome latency in these infected cells in order to expose them to antiviral therapeutics. It is not clear, however, that a specific inhibitor of HDAC3 would be effective against latency cells isolated from aviremic patients due to lack of homogeneity in the location of DNA integration of the HIV genome As the length of treatment with any HDAC inhibitor needed for effective eradication is unknown at present, side effects from non-specific epigenetic drugs is an obvious concern. Apicidin is typical of HDAC inhibitors (HDACIs) that show selectivity for an isoform, in this case HDAC3, but exhibit only 3-fold discrimination vs. HDAC2 and 11-fold vs. HDAC8. The cyclic tetrapeptide headgroup in apicidin is a source of specificity for HDAC3 and coincides with a major research interest of the Marshall lab, namely the use of constrained cyclictetrapeptides as probes of molecular recognition. An international team of experts in design, synthesis and characterization of HDAC inhibitors in overcoming HIV latency has been organized to generate specific inhibitors of HDAC isoforms, starting with HDAC3 for the potential eradication of AIDS.

Public Health Relevance

In order to eliminate infection in HIV-positive patients, latent viral reservoirs must be purged to render infected cells susceptible to antivirals. HDAC3 appears to be the primary histone deacetylase responsible for HIV latency in cell-line models, and a specific inhibitor of HDAC3 should overcome latency in infected cells in order to expose them to antiviral therapeutics. Specific inhibitors of all eleven zinc-based HDACs is the goal of this research to provide molecular scalpels to help dissect the complexity of dynamic acetylation in gene expression. An international team of experts in design, synthesis and characterization of HDAC inhibitors in overcoming HIV latency has been organized to generate specific inhibitors of HDAC isoforms, starting with HDAC3 for the potential eradication of AIDS.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM106974-02
Application #
8652488
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Sakalian, Michael
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130