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，感染艾滋病毒的成年人正在步入老年。与未感染艾滋病毒的同龄人相比，感染艾滋病毒的成年人与衰老相关的发病率更高，包括心血管疾病、癌症、神经认知能力下降和虚弱。 HIV 感染和衰老对先天性和适应性免疫衰老具有累加效应，其测量结果与衰老结果相关。 T 淋巴细胞耗竭是适应性免疫衰老与癌症和自身免疫性疾病相关的一个方面，其特征是 T 淋巴细胞细胞因子产生的改变以及 T 淋巴细胞无反应性和细胞凋亡的促进。 HIV 和衰老对 T 淋巴细胞耗竭的综合影响及其与临床衰老结果的关系尚不清楚。在本研究中，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 淋巴细胞耗竭的累加效应，(2) 检查耗竭的 T 淋巴细胞在体外产生的细胞因子作为免疫衰老的机制，以及 (3) 评估 T 淋巴细胞耗竭标志物对虚弱测量的预测效用。我们将创建一个艾滋病毒感染和未感染成年人的前瞻性队列，收集生物样本用于流式细胞术实验，并在两个时间点对虚弱和功能衰退进行临床评估。鉴于逆转 T 淋巴细胞耗竭的免疫疗法的可用性，这项研究的发现将能够立即转化为老年 HIV 感染者的预防和治疗策略。 候选人将培养转化、免疫学研究方面的技能，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者的衰老相关疾病的流行病学研究方面拥有深厚的背景。拟议的项目将为她提供以下方面的新专业知识：（1）通过研究虚弱来进行衰老综合征的临床研究；（2）通过获得慢性艾滋病毒感染的免疫效应技能来进行转化科学。职业发展活动将增强她在流行病学方面的基础，使候选人能够成为一名独立的临床研究者，从事艾滋病毒感染成人衰老结果的风险评估、预防和治疗。范德比尔特大学医学中心拥有优越的环境来支持候选人的研究生涯。她将得到博士的卓越指导的支持。 Timothy Sterling（联合导师）、Spyros Kalams（联合导师）、John Schnelle（指导委员会）和 Matthew Freiberg（指导委员会）。除了诊所和实验室外，候选人还将利用范德堡大学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）、导师计划和研究生水平课程。 我们对感染艾滋病毒的成年人的护理需要加深对衰老生物学的了解。这项研究不仅对预防和治疗衰老结果具有重要意义，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，候选人将有望成为艾滋病毒和老龄化领域的领导者。