Novel compounds that target HIV latency

Boston Medical Center, Boston MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION: 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.