Survival Factors Regulating the HIV-Specific Cytotoxic T Lymphocyte Response

描述（由申请人提供）：本提案描述了一项为期5年的指导培训计划，旨在为申请人提供细胞毒性T细胞反应和HIV病毒发病机制领域的强化培训，并提高申请人的研究技能和专业知识，以促进其作为独立研究者的发展。候选人将由资深研究人员Paul Goepfert博士和Jiri Mestecky博士指导，他们是艾滋病毒免疫学和疫苗开发领域公认的领导者。她还得到了一个多学科咨询委员会的支持，并将通过教学课程、会议和研讨会开展教育计划。她将从事一个研究项目，研究细胞凋亡在HIV感染中细胞毒性T淋巴细胞（CTL）反应中的作用，以及这如何导致免疫反应控制HIV复制失败以及调节CTL存活的因素。尽管在感染早期有一个强有力的抗原特异性细胞毒性T淋巴细胞（CTL）反应，但大多数患者对HIV复制的控制失败。了解产生和维持有效CTL应答所必需的组分对于开发有效的治疗性和预防性疫苗至关重要。我们先前已经关注应答的质量，并且已经发现能够在抗原识别后分泌细胞因子、增殖和脱粒的多功能CTL应答在急性感染中产生并在LTNP（长期非进展者）中维持。然而，不确定是什么因素有助于维持这些多功能CTL。HIV特异性CD 8 T细胞优先引发凋亡，但可能一些CTL比其他CTL对凋亡更具抗性。Bcl-2表达水平越高的CTL越能抵抗细胞凋亡。BCL又受共刺激信号如4-1BB和细胞因子（包括IL-15）调节。基于这些观察结果，我们假设来源于LTNP的CTL被维持到慢性感染，因为它们对细胞凋亡具有相对抗性。本项目旨在阐明LTNP中促进CTL存活的促凋亡因子和抗凋亡因子，并确定产生能够抵抗凋亡的有效CTL所需的共刺激信号。亚拉巴马大学医学系和微生物学/免疫学系结合了最先进的研究设施、优秀的职业发展资源和广泛的临床基础，为培养转化研究方面的医生科学家提供了理想的环境。在这种环境中，候选人将有很大的机会来丰富她的科学经验，并发展她的职业道路作为一个院士。了解艾滋病毒感染者控制病毒的有效免疫反应将有助于我们设计更好的治疗和预防疫苗。

DESCRIPTION (provided by applicant): This proposal describes a 5 year mentored training program to provide the applicant with intensive training in the areas of cytotoxic T cell responses and HIV viral pathogenesis and to advance the applicant's research skills and expertise to facilitate her development as an independent investigator. The candidate will be mentored by established investigators, Drs. Paul Goepfert and Jiri Mestecky, who are recognized leaders in immunology and vaccine development for HIV. She also has the support of a multidisciplinary advisory committee and will pursue a program of education through didactic coursework, conferences and seminars. She will engage in a research project examining the role of apoptosis in cytotoxic T lymphocyte (CTL) responses in HIV infection and how this contributes to the failure of the immune response to control HIV replication as well as factors regulating CTL survival. Despite a robust antigen-specific cytotoxic T lymphocyte (CTL) response early in infection, control of HIV replication fails in most patients. Understanding the components necessary in generating and maintaining an effective CTL response is imperative to developing effective therapeutic and preventative vaccines. We have previously focused on the quality of the response and have found that polyfunctional CTL responses, capable of cytokine secretion, proliferation and degranulation after antigen recognition, are generated in acute infection and maintained in LTNP (long term non-progressors). However, it is not certain what factors contribute to the maintenance of these polyfunctional CTL. HIV specific CDS T cells are preferentially primed for apoptosis but it is likely that some CTL are more resistant to apoptosis than others. CTL with higher levels of Bcl-2 are more resistant to apoptosis. BCL is in turn regulated by costimulatory signals such as 4-1BB and cytokines, including IL-15. Based on these observations we hypothesize that CTL derived from LTNP are maintained into chronic infection because they are relatively resistant to apoptosis. This project proposes to elucidate the pro-and anti-apoptotic factors contributing to survival of CTL in LTNP and determine the costimulatory signaling necessary to generate effective CTL capable of resisting apoptosis. The Departments of Medicine and Microbiology/Immunology at the University of Alabama provide an ideal setting for training physician scientist in translational research by combining state of the art research facilities, excellent career development resources, and a broad clinical base. In this environment, the candidate will have great opportunities to enrich her scientific experiences and develop her career path as an academician. Lay Statement- Understanding the effective immune response in HIV infected patients who control virus will help us design better therapeutic and preventative vaccines.