CONTRIBUTION OF CELLULAR FACTOR TO HIV-1 ASSEMBLY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. A. Specific Aims The global HIV epidemic continues to expand exceeding previous predictions and has become one of the deadliest epidemics in human history. The high prevalence of HIV infection in the African-American women points to the need to develop the new medical interventions toward eliminating women's health disparities in HIV/AIDS. The emergence and transmission of HIV-1 isolates resistant to currently approved drugs makes the discovery of novel anti-HIV drugs with new mechanisms and targets a high research priority. HIV-1 Gag protein directs the highly ordered process of particle assembly and release. Distinct steps involved in these late stages of the HIV-1 replication cycle are being defined, yet significant gaps still need to be filled in our knowledge. Recently, by yeast two-hybrid screening of a human cDNA library, we identified a novel Gag-binding partner, filamin A. Filamin A (FLNa) is a non-muscle actin binding protein that plays an important role in cross-linking cortical filaments into a dynamic three-dimensional structure. FLNa interacts with different cellular proteins, and serves as a versatile scaffold required for protein trafficking, signaling transduction, and cell-cell and/or cell-matrix connections. The discovery of the FLNa-Gag interaction in a productive manner in HIV-1 particle assembly and release suggests that FLNa facilitates HIV-1 Gag trafficking to the plasma membrane by regulating the actin cytoskeleton remodeling. The overall goal of this RCMI pilot project is to define the molecular basis of the FLNa-Gag interaction and its biological significance. Our studies will provide important new information regarding retrovirus-host interactions, and will impact anti-HIV therapy by discovering and developing novel assembly inhibitors. This proposal will be accomplished in a series of experiments organized within three integrated specific aims. Specific Aim 1: To define the molecular basis of the FLNa-Gag interaction. Specific Aim 2: To define the mechanism of FLNa-regulated HIV-1 Gag trafficking. Specific Aim 3: To define the role of FLNa in human primary CD4+ T cells and macrophages.