The effects of HIV gp120 on CTL migration and efficacy

描述(由申请人提供)：应聘者目前在马萨诸塞州综合医院参加她的传染病临床和研究奖学金培训的第三年。她计划在一家学术医学中心担任基础科学研究员，在临床责任的同时，专注于占主导地位的研究。完成拟议的研究培训计划的环境将为正式学习和合作提供一个有充分机会的支持性氛围，并将为候选人的独立调查职业生涯做好准备。 全世界大多数艾滋病毒感染者无法获得高效抗逆转录病毒疗法(HAART)，因此最终发展为无法控制的病毒血症和进行性疾病。HIV利用各种机制来逃避免疫系统，包括HIV特异性辅助T细胞的感染和裂解，逃逸突变的产生，以及病毒蛋白的直接作用。这一建议旨在证明HIV蛋白gp120通过与趋化因子受体CXCR4和CCR5相互作用来干扰免疫细胞的迁移，从而使HIV感染的细胞逃避宿主免疫效应细胞的攻击。H1V特异性细胞毒性T淋巴细胞(CTL)的功能效能将使用标准的移行试验以及考虑到细胞移行对杀伤效力的影响而进行修改的细胞毒性试验来评估。将定义由gp120结合的CXCR4或CCR5激活的导致CTL定位失调的信号转导通路。此外，还将设计一个小鼠模型，以检查HIV gp120-趋化因子受体相互作用对体内CTL迁移的影响。所产生的数据将扩大对为什么人类免疫系统无法控制艾滋病毒感染的理解，并理想地促进有助于根除艾滋病毒感染者体内病毒的新疗法的设计。

DESCRIPTION (provided by applicant): The candidate is currently enrolled in her third year of clinical and research fellowship training in Infectious Diseases at the Massachusetts General Hospital. She plans a career as a basic science researcher at an academic medical center with a dominant research focus complimented by clinical responsibilities. The environment in which the proposed research training program will be accomplished will provide a supportive atmosphere with ample opportunity for formal learning and collaboration, and will prepare the candidate for an independent investigative career. Most HIV-infected individuals worldwide do not have access to highly active anti-retroviral therapy (HAART) and therefore ultimately develop uncontrolled viremia and progressive disease. HIV exploits various mechanisms in order to evade the immune system including the infection and lysis of HIV-specific helper T-cells, the generation of escape mutations, and direct effects of viral proteins. This proposal aims to demonstrate that the HIV protein, gp120, interferes with immune cell migration via its interaction with the chemokine receptors CXCR4 and CCR5, thus allowing HIV-infected cells to escape challenge by host immune effector cells. The functional efficacy of H1V-specific cytotoxic T lymphocytes (CTL) will be assessed using standard transmigration assays as well as cytotoxicity assays modified to account for the effects of cell migration on killing efficacy. The signal transduction pathways, activated by gp120 binding CXCR4 or CCR5, that lead to dysregulation of CTL localization will be defined. Additionally, a murine model will be designed in order to examine the effects of HIV gp120---chemokine receptor interaction on CTL migration in an in vivo setting. Data generated will expand the understanding of why the human immune system fails to contain HIV infection, and ideally facilitate the design of novel therapies that will assist in the eradication of the virus in HIV-infected individuals.