Regulatuion of HIV-1 Gene Expression in Latency by YY1, RuvB2, and ZAP

Columbia University Health Sciences, New York NY

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Abstract

DESCRIPTION (provided by applicant): With Highly Active AntiRetroviral Therapy (HAART), HIV-1 replication can be controlled to maintain a plasma level of viral RNA below detection by conventional means. However, the continued presence of silent HIV-1 proviral DNA in memory CD4+ T cells is a major barrier to the eradication of the virus in AIDS patients. Multiple mechanisms have been reported by which HIV-1 proviruses are maintained in a silent state in these cells. The major block to active viral replication is believed to be at the transcriptional level. However, viral RNAs can be detected in long-term HAART-treated patients by sensitive detection methods, suggesting that transcriptional control may not be the only mechanism underlying the maintenance of viral latency. This project now aims to understand the post-transcriptional control of HIV-1 gene expression mediated by three regulatory systems: the Nonsense Mediated Decay (NMD) system; a repressor of HIV translation (RVB2) which we have recently identified; and the Zinc- finger Antiviral Protein (ZAP) which silences and triggers degradation of many viral RNAs. We will specifically explore the possible role of each of these systems in the maintenance of HIV-1 latency. We will examine the levels of HIV-1 RNA and protein expression in CD4-positive memory T cells from HIV-1 infected patients after manipulating the functions of each of these regulatory systems using siRNA knockdown technology. Discovery of the major mechanisms controlling post-transcriptional regulation of HIV-1 gene expression is an essential first step toward the release of repression and the activation of viral replication. This activation will permit the detection of virus-infected cells y the immune system and facilitate the clearance of infected cells by therapies that target viral proteins expressed in and on the surface of memory T cells.