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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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AIDS Molecular and Cellular Biology Study Section (AMCB)
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Sanders, Brigitte E
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George Mason University
Schools of Arts and Sciences
United States
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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
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
Spear, Mark; Guo, Jia; Wu, Yuntao (2013) Novel anti-HIV therapeutics targeting chemokine receptors and actin regulatory pathways. Immunol Rev 256:300-12
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
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
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Guo, Jia; Enos, Clinton; Wu, Yuntao (2010) Specific marking of HIV-1 positive cells using a Rev-dependent lentiviral vector expressing the green fluorescent protein. J Vis Exp :
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Wu, Yuntao (2010) Chemokine control of HIV-1 infection: beyond a binding competition. Retrovirology 7:86

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