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.