Although Combination Antiretroviral Therapy (cART) is very potent in suppressing HIV replication and therefore life-prolonging, it can't eradicate HIV 1 infection. HIV can persist in long-lived resting memory CD4+ T cells. This reservoir of latent HIV-1 proviruses is the principal impediment to eradication of HIV infection. The current widely discussed and tested approach to eliminate the latent reservoirs is the so-called sock and kill strategy. It is hypothesized that reactivating latent HIV ('shock') in the presence of cART and immune-based therapy would ('kill') purge these reservoirs. In eukaryotic cells, the level of gene expression is strictly regulated by epigenetic modifications on chromatin including histone modifications and DNA methylation. The repressive status of chromatin largely contributes to HIV latency. In this proposal, we have identified a novel molecular mechanism of repressing HIV-LTR mediated transcription at epigenomic level. Importantly, we found that a small molecule inhibitor of a key epigenetic enzyme could reactivate HIV in two HIV latency cell models. In the R21 phase of this proposal, we will (1) further dissect the molecular basis of epigenetic regulation of HIV latency, and (2) evaluate our small molecular inhibitor in a primary CD4+ T cells model. In the R33 phase, using our small molecular inhibitor as a prototype, we will develop more specific and potent small molecule inhibitors, and determine whether these compounds can reactivate latent HIV in patients' samples. The potential synergistic effect of our compounds with other established HIV latency- reversing agents will also be evaluated. In summary, our proposed studies will likely uncover new mechanisms of regulation of HIV latency at the epigenomic level. Most importantly, based on our mechanistic studies, we might be able to develop a novel class of epigenetic compounds for reactivation of the latent HIV.

Public Health Relevance

In this project, we have identified a novel epigenetic enzyme as a negative regulator of HIV transcription. Inhibition of this protein by a small molecule inhibitor re-activated latent HIV in cell models. Our results suggest a novel epigenomic approach for the treatment of AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
5R33AI122418-05
Application #
9616811
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Miller, Roger H
Project Start
2018-08-13
Project End
2020-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Houston
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
036837920
City
Houston
State
TX
Country
United States
Zip Code
77204