The effects of HIV gp120 on CTL migration and efficacy

HIV gp120对CTL迁移和功效的影响

• 批准号: 6842304
• 负责人: DIANA M BRAINARD
• 金额: $ 11.45万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6842304
• 关键词: AIDS; HIV envelope protein gp120; HIV infections; biological signal transduction; cell line; cell migration; cellular immunity; chemokine receptor; clinical research; cytotoxic T lymphocyte; flow cytometry; fluorimetry; host organism interaction; human subject; immune response; intermolecular interaction; pathologic process; receptor binding; video microscopy; virus infection mechanism; virus replication

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.

描述（由申请人提供）：候选人目前在马萨诸塞州总医院参加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，主要研究重点是临床责任。拟议的研究培训计划将完成的环境将提供一个支持性的氛围，有充分的机会进行正式的学习和合作，并将为候选人的独立调查生涯做好准备。 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治疗（HAART），因此最终发展为不受控制的病毒血症和疾病进展。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。该提案旨在证明HIV蛋白gp 120通过与趋化因子受体CXCR 4和CCR 5的相互作用干扰免疫细胞迁移，从而使HIV感染的细胞逃避宿主免疫效应细胞的攻击。H1 V特异性细胞毒性T淋巴细胞（CTL）的功能效力将使用标准迁移测定以及经修改以解释细胞迁移对杀伤效力的影响的细胞毒性测定来评估。将定义由gp 120结合CXCR 4或CCR 5激活的导致CTL定位失调的信号转导途径。此外，将设计小鼠模型，以检查HIV gp 120-趋化因子受体相互作用对体内环境中CTL迁移的影响。所产生的数据将扩大对人类免疫系统为何无法遏制艾滋病毒感染的理解，并理想地促进新疗法的设计，这将有助于根除艾滋病毒感染者中的病毒。