Binding of the HIV-1 envelope to chemokine coreceptors mediates two major biological events: membrane fusion and signal transduction. The fusion process has been well characterized. Yet the role of coreceptor signaling in HIV-1 infection remained elusive. In my dissertation, I present a summary of my investigation into the mechanism of how chemokine coreceptor signaling facilitates HIV-1 infection of human resting CD4 T cells. In human T cells, chemokine receptor signaling is directly linked to cytoskeletal remodeling, thus, I hypothesized that the actin dynamics driven through HIV envelopeCXCR4 signaling could be important for HIV-1 infection of T cells. My study revealed that inhibition of HIV-mediated actin change markedly diminishes viral latent infection of resting T cells, confirming a critical role of actin dynamics in HIV infection of resting T cells. Moreover, I discovered that HIV-1 uses CXCR4 signaling to activate a cellular actin depolymerizing factor, cofilin, to increase actin dynamics. Induction of cofilin activation in resting CD4 T cells greatly enhanced HIV-1 infection of resting CD4 T cells. Overall, these results provide a mechanism of how HIV-1 exploits the chemokine receptor signaling to alter the cellular environment in its favor. Given the critical role of cofilin in T cell activation and chemotaxis, my study of cofilin activation in HIV-1 infection has numerous implications for HIV-1 pathogenesis in T cells in vivo.
|School:||George Mason University|
|School Location:||United States -- Virginia|
|Source:||DAI-B 68/06, Dissertation Abstracts International|
|Subjects:||Molecular biology, Cellular biology, Virology|
|Keywords:||Actin, CD4 T cells, CXCR4, Cofilin, HIV-1 envelope|
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