Mechanisms of Action of Novel HIV Rev Co-factors

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DESCRIPTION (provided by applicant): The HIV Rev protein is essential for viral replication and it functions to export unspliced viral RNA from the nucleus to the cytoplasm. A key cellular co-factor for Rev is the CRM1 protein (also named XPO1). The mining of a database of human nuclear protein complexes led to the identification of two proteins that associate with CRM1-- RBM14 and PACS1. SiRNA depletions experiments revealed that both RBM14 and PACS1 are required for Rev activation of two different Rev-reporter plasmids, but not for reporter plasmids dependent upon the Constitutive Transport Element (CTE) or MMTV Rev RNA export pathways. Depletion of either protein reduces the level of unspliced viral RNA in the cytoplasm, but leads to an increase in unspliced viral RNA in the nucleus. The proposed research will investigate the mechanistic roles of RBM14 and PACS1 in Rev function. This research will provide mechanistic insight into HIV Rev function, and this may provide information leading to novel therapeutic strategies for HIV infection. Additionally, the proposed work is likely to shed insight into genera mechanisms of RNA export and this may have relevance to other human diseases.