Regulation of Cofilin in HIV-1 Infection of Human CD4 T Cells

描述（由申请人提供）：HIV-1感染CD 4 T细胞，导致T细胞耗竭和免疫缺陷。病毒与T细胞之间的分子相互作用在早期发生，对于病毒感染和发病至关重要。我们的初步研究已经确定cofilin是病毒靶向的早期信号分子之一，以建立CD 4 T细胞的潜伏感染。我们已经证明，HIV-1利用病毒包膜/CXCR 4信号传导来激活cofilin，以克服静息CD 4 T细胞中的皮质肌动蛋白限制。这种分子事件对于静息T细胞中的病毒核迁移是必要的。我们的长期目标是研究导致异常信号传导和cofilin激活的病毒-宿主相互作用的分子细节。该提案的具体目的是研究病毒包膜gp 120及其趋化因子辅助受体CXCR 4之间的相互作用，从而导致cofilin激活。我们将识别gp 120上的信号结构域，并绘制相关的信号通路。这项拟议中的研究意义重大，因为这些信息将有助于确定被病毒劫持以促进感染的特定细胞机制。这些机制与CD 4 T细胞中的病毒发病机制高度相关。拟议研究的结果也可能确定新的治疗靶点，以抑制病毒感染。公共卫生相关性：HIV-1感染导致艾滋病，全球约有4000万人感染艾滋病。这项拟议的研究将有助于确定被HIV-1劫持以促进病毒感染的特定细胞机制。这些机制对于理解病毒的发病机制非常重要，并将有助于确定治疗HIV-1感染的新靶点。

DESCRIPTION (provided by applicant): 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.