The dynamics of HIV, aging, and T lymphocyte exhaustion

HIV、衰老和 T 淋巴细胞耗竭的动态

• 批准号: 9252841
• 负责人: Jessica L Castilho
• 金额: $ 16.02万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9252841
• 关键词: Academic Medical Centers; Adult; Affect; Age; Aging; Apoptosis; Autoimmune Diseases; Award; Biology of Aging; Cardiovascular Diseases; Caring; Cell Aging; Chronic; Clinic; Clinical; Clinical Investigator; Clinical Research; Clinical Sciences; Collection; Development; Disease; Elderly; Environment; Epidemiologic Studies; Epidemiology; Etiology; Flow Cytometry; Foundations; Future; HIV; HIV Infections; HIV vaccine; Health; Immune; Immune system; Immunologics; Immunology; Immunotherapy; Impaired cognition; In Vitro; Inflammation; Intervention; Knowledge; Laboratories; Life; Lymphocyte; Lymphocyte Activation; Malignant Neoplasms; Measures; Mentors; Mentorship; Monoclonal Antibodies; Morbidity - disease rate; Neurocognitive Deficit; Outcome; Participant; Persons; Population; Prevention; Prevention strategy; Preventive treatment; Production; Research; Research Design; Research Personnel; Resources; Rest; Risk; Risk Assessment; Science; Syndrome; T lymphocyte marker; T-Lymphocyte; Time; Translational Research; Translations; age effect; age related; anergy; antiretroviral therapy; base; career; career development; clinical investigation; cohort; cytokine; cytotoxic; exhaust; exhaustion; experience; frailty; functional decline; functional status; improved; peer; prevent; programs; prospective; public health relevance; receptor; research clinical testing; research study; senescence; skills; success; therapy development; translational study; treatment strategy

 DESCRIPTION (provided by applicant): With the success of antiretroviral therapy, HIV-infected adults are living into older age. Compared to their uninfected peers, HIV-infected adults suffer from increased rates morbidity associated with aging including cardiovascular disease, cancer, neurocognitive decline, and frailty. HIV infection and aging have additive effects on innate and adaptive immune senescence, measures of which been associated with aging outcomes. An aspect of adaptive immune senescence that has been associated with cancer and autoimmune disorders, T lymphocyte exhaustion is characterized by alteration in T lymphocyte cytokine production and promotion of T lymphocyte anergy and apoptosis. The combined effects of HIV and aging on T lymphocyte exhaustion and its association with clinical aging outcomes are unknown. In this study, the candidate aims to answer these questions by (1) measuring the additive effects of HIV and aging on T lymphocyte cellular exhaustion, (2) examining in vitro cytokine production by exhausted T lymphocytes as a mechanism of immune senescence, and (3) assessing the predictive utility of T lymphocyte markers of exhaustion on measures of frailty. We will create a prospective cohort of HIV-infected and -uninfected adults, collect biospecimens for flow cytometry experiments, and assesses clinically for frailty and functional decline at two time points. Given the availability of immune therapies to reverse T lymphocyte exhaustion, discoveries from this study will allow for immediate translation into preventive and treatment strategies for aging HIV-infected adults. The candidate will develop skills in translational, immunologic research to become an independent investigator in the clinical investigation of HIV and aging. The candidate has a strong background in epidemiologic research of aging-related diseases in HIV-infected adults. The proposed project will afford her new expertise in (1) clinical research in aging syndromes through the study of frailty and (2) translational science by acquiring skills in immunologic effects of chronic HIV infection. Adding to her foundation in epidemiology, the career development activities will enable the candidate to become an independent clinical investigator in risk assessment, prevention, and treatment of aging outcomes in HIV-infected adults. Vanderbilt University Medical Center has a superb environment to support the candidate's research career. She will be supported by exceptional mentorship by Drs. Timothy Sterling (co-mentor), Spyros Kalams (co-mentor), John Schnelle (mentoring committee), and Matthew Freiberg (mentoring committee). In addition to clinics and laboratories, the candidate will utilize Vanderbilt's outstanding resources for young investigators including its Clinical and Translational Science Award (CTSA), mentorship programs, and graduate-level courses. Our care of HIV-infected adults requires improved understanding of the biology of aging. This study has important implications not only for prevention and treatment of aging outcomes but also for vaccine and HIV cure research. Through this award, the candidate will be poised to become a leader in HIV and aging.

 描述（由适用提供）：随着抗逆转录病毒疗法的成功，感染了HIV的成年人已经生活了。与未感染的同龄人相比，感染HIV的成年人患有与衰老有关的发病率增加，包括心血管疾病，癌症，神经认知能力下降和脆弱。 HIV感染和衰老对先天性和适应性免疫纪念性具有额外的影响，其措施与衰老结局有关。与癌症和自身免疫性疾病有关的适应性免疫纪念腺的一个方面，T淋巴细胞衰竭的特征是T淋巴细胞细胞因子产生的改变以及促进T淋巴细胞厌食和凋亡的促进。艾滋病毒和衰老对T淋巴细胞耗尽的综合作用及其与临床衰老结局的关联尚不清楚。 In this study, the candidate aims to answer these questions by (1) measuring the additive effects of HIV and aging on T lymphocyte cellular exhaustion, (2) examining in vitro Cytokine production by exhausted T lymphocytes as a mechanism of immunosenscence, and (3) assessing the predictive utility of T lymphocyte markers of exhaustion on measurements of frailty.我们将创建一个前瞻性的HIV感染和未感染的成年人，收集用于流式细胞仪实验的生物测量，并在两个时间点上评估临床上的脆弱和功能下降。鉴于免疫疗法可用于逆转淋巴细胞的疲劳，这项研究的发现将立即转化为衰老的HIV感染的成年人的预防和治疗策略。候选人将发展转化，免疫学研究的技能，成为艾滋病毒和衰老临床研究的独立研究者。该候选人在艾滋病毒感染的成年人的衰老相关疾病的流行病学研究方面具有强大的背景。拟议的项目将通过（1）通过脆弱和（2）转化科学的研究获得（1）在衰老综合症的临床研究方面提供新的专业知识，并通过获得慢性HIV感染的免疫学影响技能。除了她的流行病学基础外，职业发展活动将使候选人能够成为风险评估，预防和治疗艾滋病毒感染的成年人衰老结果的独立临床研究者。范德比尔特大学医学中心有一个极好的环境来支持候选人的研究生涯。博士将受到杰出的心态的支持。蒂莫西·斯特林（Co-Encortor），Spyros Kalams（Co-Incertor），John Schnelle（指导委员会）和Matthew Freiberg（指导委员会）。除诊所和实验室外，候选人还将利用范德比尔特为年轻调查人员提供的杰出资源，包括其临床和转化科学奖（CTSA），Mentalship计划和研究生级课程。我们对感染HIV的成年人的护理需要提高人们对衰老的生物学的了解。这项研究不仅对预防和治疗衰老结局具有重要意义，而且对疫苗和艾滋病毒治疗研究也具有重要意义。通过该奖项，候选人将被毒死成为艾滋病毒和衰老的领导者。