The dynamics of HIV, aging, and T lymphocyte exhaustion

 描述(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进入高龄。与未感染的同龄人相比，感染艾滋病毒的成年人与年龄相关的发病率增加，包括心血管疾病、癌症、神经认知能力下降和虚弱。艾滋病毒感染和衰老对先天和获得性免疫衰老具有相加作用，其程度与衰老结果相关。T淋巴细胞衰竭是与癌症和自身免疫性疾病相关的获得性免疫衰老的一个方面，其特征是T淋巴细胞细胞因子的产生发生改变，促进T淋巴细胞无能和细胞凋亡。艾滋病毒和衰老对T淋巴细胞耗竭的联合影响及其与临床衰老结局的关系尚不清楚。在这项研究中，候选人旨在通过以下方式回答这些问题：(1)测量艾滋病毒和衰老对T淋巴细胞细胞衰竭的相加效应；(2)体外检测衰竭T淋巴细胞产生的细胞因子作为免疫衰老的机制；(3)评估T淋巴细胞衰竭标志物对衡量脆弱程度的预测作用。我们将建立HIV感染和未感染成人的预期队列，收集用于流式细胞术实验的生物标本，并在两个时间点对虚弱和功能下降进行临床评估。鉴于免疫疗法可以逆转T淋巴细胞衰竭，这项研究的发现将使人们能够立即将其转化为老年艾滋病毒感染成年人的预防和治疗策略。应聘者将发展翻译、免疫学研究方面的技能，成为艾滋病毒和老龄化临床调查的独立调查员。应聘者在艾滋病毒感染成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。拟议的项目将为她提供(1)通过研究虚弱来研究衰老综合征的临床研究，以及(2)通过获得慢性艾滋病毒感染的免疫学影响的技能来进行翻译科学的新专业知识。除了她在流行病学方面的基础外，职业发展活动将使应聘者能够成为一名独立的临床调查员，负责艾滋病毒感染成年人衰老后果的风险评估、预防和治疗。范德比尔特大学医学中心拥有一流的环境来支持候选人的研究生涯。她将得到Timothy Sterling博士(联合导师)、Spyros Kalams博士(联合导师)、John Schnelle博士(导师委员会)和Matthew Freiberg博士(导师委员会)的杰出导师的支持。除了诊所和实验室，候选人还将利用范德比尔特为年轻研究人员提供的杰出资源，包括临床和转化科学奖(CTSA)、导师计划和研究生水平的课程。我们对感染艾滋病毒的成年人的护理需要更好地理解衰老的生物学。这项研究不仅对预防和治疗老龄化结果具有重要意义，而且对疫苗和HIV治愈研究也有重要意义。通过这个奖项，这位候选人将成为艾滋病毒和老龄化领域的领导者。

 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.