HIV-1 infects CD4 T cells and causes T cell depletion and immunodeficiency. Molecular interactions between the virus and T cells that occur at the early time are critical for viral infection and pathogenesis. Our preliminary studies have identified cofilin as one of the early signaling molecules targeted by the virus in order to establish latent infection of CD4 T cells. We have demonstrated that HIV-1 utilizes the viral envelope/CXCR4 signaling to activate cofilin in order to overcome the cortical actin restriction in resting CD4 T cells. This molecular event is necessary for viral nuclear migration in resting T cells. Our long-term goal is to study the molecular details of viral-host interaction that lead to aberrant signaling and cofilin activation.
The specific aims of this proposal are to study the interactions between the viral envelope, gp120, and its chemokine coreceptor, CXCR4, that lead to cofilin activation. We will identify the signaling domains on gp120, as well as map the signaling pathways involved. This proposed research is significant because the information will help to identify specific cellular mechanisms hijacked by the virus to facilitate infection. These mechanisms are highly relevant to viral pathogenesis in CD4 T cells. Results from the proposed study may also identify novel therapeutic targets to inhibit viral infection.
HIV-1 infection causes AIDS that afflicted approximately 40 million people globally. This proposed research will help to identify specific cellular mechanisms hijacked by HIV-1 to facilitate viral infection. These mechanisms are very important to understand viral pathogenesis and will help to identify novel therapeutic targets to treat HIV-1 infection.
|Spear, Mark; Guo, Jia; Turner, Amy et al. (2014) HIV-1 triggers WAVE2 phosphorylation in primary CD4 T cells and macrophages, mediating Arp2/3-dependent nuclear migration. J Biol Chem 289:6949-59|
|Li, Zichong; Guo, Jia; Wu, Yuntao et al. (2013) The BET bromodomain inhibitor JQ1 activates HIV latency through antagonizing Brd4 inhibition of Tat-transactivation. Nucleic Acids Res 41:277-87|
|Spear, Mark; Guo, Jia; Wu, Yuntao (2013) Novel anti-HIV therapeutics targeting chemokine receptors and actin regulatory pathways. Immunol Rev 256:300-12|
|Guo, Jia; Xu, Xuehua; Rasheed, Taban K et al. (2013) Genistein interferes with SDF-1- and HIV-mediated actin dynamics and inhibits HIV infection of resting CD4 T cells. Retrovirology 10:62|
|Wang, Weifeng; Guo, Jia; Yu, Dongyang et al. (2012) A dichotomy in cortical actin and chemotactic actin activity between human memory and naive T cells contributes to their differential susceptibility to HIV-1 infection. J Biol Chem 287:35455-69|
|Spear, Mark; Guo, Jia; Wu, Yuntao (2012) The trinity of the cortical actin in the initiation of HIV-1 infection. Retrovirology 9:45|
|Guo, Jia; Xu, Xuehua; Yuan, Wen et al. (2012) HIV gp120 is an aberrant chemoattractant for blood resting CD4 T cells. Curr HIV Res 10:636-42|
|Guo, Jia; Wang, Weifeng; Yu, Dongyang et al. (2011) Spinoculation triggers dynamic actin and cofilin activity that facilitates HIV-1 infection of transformed and resting CD4 T cells. J Virol 85:9824-33|
|Vorster, Paul J; Guo, Jia; Yoder, Alyson et al. (2011) LIM kinase 1 modulates cortical actin and CXCR4 cycling and is activated by HIV-1 to initiate viral infection. J Biol Chem 286:12554-64|
|Yoder, Alyson; Guo, Jia; Yu, Dongyang et al. (2011) Effects of microtubule modulators on HIV-1 infection of transformed and resting CD4 T cells. J Virol 85:3020-4|
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