Long lived latently infected cells, which include quiescent memory T cells and macrophages, present a major barrier to eliminating HIV infection since they act as sanctuaries for repressed or inactivated HIV provirus and serve as a source of virus rebound following interruption of treatment. One potential strategy is to use compounds that activate HIV transcription and purge virus from these HIV reservoirs, although early efforts have had modest success, possibly reflecting that the establishment and maintenance of HIV latency represents combinatorial mechanisms that limit HIV transcription. Using a high throughput screen we have identified a set of benzazoles compounds that induce HIV transcription in the absence of T cell activation and proliferation. Preliminary data indicate that these compounds do not act by inhibiting NF-kB signaling or HDAC activity suggesting that a novel biochemical pathway upstream of HIV transcription is being targeted. To fully appreciate the efficacy of these compounds, we are proposing to determine the mechanisms of action for benzazoles on HIV transcription and replication using a combination of biochemical, cellular, genomic and proteomic approaches. In addition to validating the potential of these compounds for targeting HIV latency, we will use these compounds as chemical probes to discover molecular pathways that regulate HIV transcription and latency.

Public Health Relevance

Cells latently infected with HIV present a major barrier to eliminating HIV infection since these cells serve as a repository for virus late in disease and upon treatment interruption. We have identified a class of compounds which potently induce HIV transcription without activating T cells. This proposal is designed to identify and characterize th mode of action of these new compounds with a long term objective of determining how these small molecules can be used as part of a combinatorial approach with existing treatments to control and possibly even eradicate HIV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI108447-01A1
Application #
8659640
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Sharma, Opendra K
Project Start
2014-07-10
Project End
2016-06-30
Budget Start
2014-07-10
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$231,397
Indirect Cost
$89,064
Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118