P-TEFb and HIV Latency

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DESCRIPTION (provided by applicant): Combinations of current anti-HIV-1 drugs suppress virus replication to undetectable levels in many patients. However, these patients possess a reservoir of cells harboring latent HIV-1 proviruses that spontaneously reactivate upon cessation of anti-viral drugs, thereby precluding a cure of infection. The best described latent reservoir is that of long-lived memory CD4+ T lymphocytes which contain a transcriptionally silent but replication competent provirus. Although mechanisms involved in latency in CD4+ T lymphocytes are incompletely understood, it is believed that multiple mechanisms act in concert to establish and maintain latency. Transcriptional interference by cellular genes at the site of integration can contribute to latency. Repressive chromatin is established for latent proviruses. Limiting levels of cellular transcription factors also make important contributions to latency, especially P-TEFb, a transcriptional elongation factor involved in the viral Tat protein's function Core P-TEFb is composed of Cyclin T1 (CCNT1) and CDK9. Recent results in a primary CD4+ T lymphocyte system of HIV-1 latency have shown that CCNT1 protein and CDK9 T-loop phosphorylation levels are down-regulated as latency is established. Conversely, CCNT1 and T-loop phosphorylation are up- regulated in this system when latent viruses are induced by T cell activation. These findings suggest that down-regulation of CCNT1 is an important and perhaps essential event in the establishment of latency. The research proposed here will test the hypothesis that down-regulation of P-TEFb can drive HIV-1 latency in CD4+ T lymphocytes. The research will also investigate mechanisms involved in the down-regulation of CCNT1 and mechanisms that regulate CDK9 T-loop phosphorylation in resting and activated CD4+ T lymphocytes. Finally, the research will determine if selective up-regulation of P-TEFb can contribute to reactivation of latent HIV-1 in a primary cell system of latency. Completion of the research will determine if P- TEFb is a key cellular factor for establishment and maintenance of HIV-1 latency. The research has the potential to establish P-TEFb as an important therapeutic target to reactivate latent viruses and thereby cure HIV-1 infection.