HIV-1 REV PROTEIN--BIOCHEMICAL MECHANISMS

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DESCRIPTION: HIV-1 Rev protein is required for viral replication and acts by facilitating this cytoplasmic accumulation of incompletely-spliced viral mRNA that encodes structural proteins. Rev is a sequence-specific RNA binding protein which interacts with the viral RNA element designated RRE. The two long-term objectives of this application are to: 1) Understand how Rev facilitates viral mRNA transport and 2) to develop small molecules and protein-based Rev inhibitors. Over the previous period of funding, a significant advance has been the cloning of a human Rev cofactor (hRIP) which is a major focus of this application. The investigator proposes to study in greater detail how Rev and hRIP collaborate to facilitate export of HIV-1 RNAs. The process of cellular mRNA nuclear export is poorly understood and this will be a major portion of the application. The second major objective is to develop Rev inhibitors. This laboratory has demonstrated certain small molecules, such as specific aminoglycoside antibiotics, which interact with the RRE to inhibit Rev binding and Rev function. Further studies on these small molecular RNA interactions will be evaluated in this application. Finally, the investigator has recently discovered methodologies to select artificial peptides to specifically interact with Rev within cells and may block Rev function. These studies will be extended and the development of more potent and specific Rev inhibitors is proposed.