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

描述（由申请人提供）：HIV-1感染CD4 T细胞并导致T细胞耗竭和免疫缺陷。早期发生的病毒和T细胞之间的分子相互作用对病毒感染和发病至关重要。我们的初步研究已经确定了cofilin作为病毒的早期信号分子之一，以建立CD4 T细胞的潜伏感染。我们已经证明HIV-1利用病毒包膜/CXCR4信号激活cofilin，以克服静息CD4 T细胞中的皮质肌动蛋白限制。这一分子事件是静止T细胞中病毒核迁移所必需的。我们的长期目标是研究导致异常信号和cofilin激活的病毒-宿主相互作用的分子细节。本提案的具体目的是研究病毒包膜gp120与其趋化因子辅助受体CXCR4之间的相互作用，从而导致cofilin激活。我们将识别gp120上的信号域，并绘制所涉及的信号通路。这项拟议的研究意义重大，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。这些机制与病毒在CD4 T细胞中的发病机制高度相关。该研究的结果还可能确定抑制病毒感染的新治疗靶点。公共卫生相关性：艾滋病毒-1感染导致艾滋病，全球约有4 000万人受其折磨。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。这些机制对于了解病毒的发病机制非常重要，并将有助于确定治疗HIV-1感染的新治疗靶点。

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.