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（由申请人提供）：随着抗逆转录病毒治疗的成功，艾滋病毒感染的成年人正在进入老年。与未感染艾滋病毒的同龄人相比，感染艾滋病毒的成年人患上与衰老有关的疾病的比率增加，包括心血管疾病、癌症、神经认知能力下降和虚弱。艾滋病毒感染和衰老对先天性和适应性免疫衰老有累加效应，其测量与衰老结果相关。与癌症和自身免疫性疾病相关的适应性免疫衰老的一个方面，T淋巴细胞耗竭的特征在于T淋巴细胞细胞因子产生的改变和T淋巴细胞无反应性和凋亡的促进。HIV和衰老对T淋巴细胞耗竭的联合作用及其与临床衰老结果的关系尚不清楚。在这项研究中，候选人旨在通过以下方式回答这些问题：（1）测量HIV和衰老对T淋巴细胞细胞耗竭的累加效应，（2）检查耗竭T淋巴细胞的体外细胞因子产生作为免疫衰老的机制，以及（3）评估T淋巴细胞耗竭标记物对虚弱测量的预测效用。我们将建立一个HIV感染和未感染成人的前瞻性队列，收集生物标本进行流式细胞术实验，并在两个时间点对虚弱和功能下降进行临床评估。考虑到逆转T淋巴细胞耗竭的免疫疗法的可用性，这项研究的发现将允许立即转化为老年艾滋病毒感染成年人的预防和治疗策略。 候选人将发展翻译，免疫学研究的技能，成为艾滋病毒和衰老临床研究的独立调查员。候选人在艾滋病毒感染成年人中与衰老相关的疾病的流行病学研究方面有很强的背景。该项目将为她提供新的专业知识：（1）通过研究脆弱性进行衰老综合征的临床研究;（2）通过获得慢性HIV感染的免疫学影响技能进行转化科学。除了她在流行病学方面的基础外，职业发展活动将使候选人能够成为独立的临床研究人员，从事艾滋病毒感染成年人衰老结局的风险评估、预防和治疗。范德比尔特大学医学中心有一个极好的环境，以支持候选人的研究生涯。她将得到Timothy Sterling博士（共同导师）、Spyros Kalams博士（共同导师）、John Schnelle博士（指导委员会）和Matthew弗赖贝格博士（指导委员会）的特别指导。除了诊所和实验室外，候选人还将利用范德比尔特为年轻研究人员提供的优秀资源，包括临床和转化科学奖（CTSA）、导师计划和研究生课程。 我们对感染艾滋病毒的成年人的护理需要更好地了解衰老的生物学。这项研究不仅对预防和治疗衰老结果，而且对疫苗和艾滋病毒治疗研究具有重要意义。通过这个奖项，候选人将准备成为艾滋病毒和老龄化的领导者。