Survival Factors Regulating the HIV-Specific Cytotoxic T Lymphocyte Response

调节 HIV 特异性细胞毒性 T 淋巴细胞反应的生存因素

• 批准号: 7338916
• 负责人: SONYA L HEATH
• 金额: $ 12.78万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7338916
• 关键词: Acute; Advisory Committees; Alabama; Antigens; Apoptosis; Apoptotic; Area; Arts; BCL1 Oncogene; Cell Death; Cells; Chronic; Clinical; Cytotoxic T-Lymphocytes; Development; Education; Environment; Failure; Generations; HIV; HIV Infections; HIV vaccine; Immune; Immune response; Immunology; Individual; Infection; Infection Control; Interleukin-15; Interleukin-2; Interleukin-7; Maintenance; Mediating; Medicine; Mentors; Microbiology; Pathway interactions; Patients; Peptides; Peripheral Blood Mononuclear Cell; Physicians; Plasma; Proteins; Research; Research Personnel; Research Project Grants; Resistance; Resource Development; Role; Scientist; Signal Transduction; Sorting - Cell Movement; Surface; T memory cell; T-Lymphocyte; Testing; Therapeutic; Training; Training Programs; Translational Research; Universities; Vaccines; Viral; Viral Load result; Viral Pathogenesis; Virus; base; career; cohort; cytokine; cytotoxic; design; experience; improved; inhibitor/antagonist; mouse model; multidisciplinary; programs; research facility; response; skills; symposium; vaccine development

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.

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，以促进她作为独立研究者的发展。候选人将受到知名研究人员 Drs 的指导。 Paul Goepfert 和 Jiri Mestecky 是公认的艾滋病毒免疫学和疫苗开发领域的领导者。她还得到了多学科咨询委员会的支持，并将通过教学课程、会议和研讨会来推行教育计划。她将参与一个研究项目，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无法控制 HIV 复制以及调节 CTL 存活的因素。尽管在感染早期存在强烈的抗原特异性细胞毒性 T 淋巴细胞 (CTL) 反应，但大多数患者无法控制 HIV 复制。了解产生和维持有效 CTL 反应所需的组成部分对于开发有效的治疗和预防疫苗至关重要。我们之前关注的是反应的质量，发现多功能 CTL 反应能够在抗原识别后分泌细胞因子、增殖和脱粒，在急性感染中产生，并在 LTNP（长期非进展者）中维持。然而，尚不清楚哪些因素有助于维持这些多功能 CTL。 HIV 特异性 CDS T 细胞优先引发细胞凋亡，但某些 CTL 可能比其他细胞更能抵抗细胞凋亡。 Bcl-2 水平较高的 CTL 更能抵抗细胞凋亡。 BCL 反过来又受到共刺激信号（例如 4-1BB 和细胞因子，包括 IL-15）的调节。基于这些观察，我们假设源自 LTNP 的 CTL 能够维持到慢性感染，因为它们对细胞凋亡相对具有抵抗力。该项目旨在阐明有助于 LTNP 中 CTL 存活的促凋亡因素和抗凋亡因素，并确定产生能够抵抗细胞凋亡的有效 CTL 所需的共刺激信号传导。阿拉巴马大学医学和微生物学/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，为转化研究领域的医师科学家培训提供了理想的环境。在这种环境下，候选人将有很大的机会丰富自己的科学经验并发展自己的院士职业道路。外行声明 - 了解控制病毒的 HIV 感染患者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。