Imaging-base Automated Screen for Compounds that Induce P-TEFb

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Although combinations of anti-HIV drugs can effectively suppress virus replication, a reservoir of cells harboring latent HIV-1 precludes a cure of infection. The best described latent reservoir consists of long-lived memory CD4+ T cells that contain a transcriptionally silent but replication-competent provirus. Multiple mechanisms are involved in the establishment and maintenance of latency, especially limiting levels of the key RNA Polymerase II elongation factor termed P-TEFb. Core P-TEFb consists of Cyclin T1 as a regulatory subunit and CDK9 as the catalytic subunit. The proposed research will optimize and perform an imaging- based automated screen for compounds that induce P-TEFb in resting CD4+ T cells. Compounds that score positive in this screen will be validated in immunoblots for the ability to induce P-TEFb in resting CD4+ T cells, as well as for their ability to function as latency reversal agents in a primary CD4+ T cell model of latency. Compounds identified by this novel screen have the potential to contribute to HIV cure strategies.