With the success of antiretroviral therapy, HIV-infected adults are living into older age. Compared to their uninfected peers, HIV-infected adults suffer from high rates of diseases associated with aging including cardiovascular disease, cancer, neurocognitive decline, and frailty. HIV infection and aging have synergistic effects on innate and adaptive immune senescence, measures of which have 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 three 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), Laura Dugan (mentoring committee) John Schnelle (mentoring committee), and Matthew Freiberg (mentoring committee). 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.

Public Health Relevance

HIV-infected adults are living into older age but often with many health complications, including cardiovascular disease, cancer, and functional decline. We do not fully understand how chronic HIV infection affects the immune system in older age, and further understanding of these changes could help identify persons at risk for serious non-infectious health complications. This knowledge will improve prevention and treatment of these diseases in HIV-infected adults and inform HIV vaccine and cure research.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AI120875-04
Application #
9440956
Study Section
Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
Program Officer
Huebner, Robin E
Project Start
2016-03-01
Project End
2021-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
Coelho, Lara; Rebeiro, Peter F; Castilho, Jessica L et al. (2018) Early Retention in Care Neither Mediates Nor Modifies the Effect of Sex and Sexual Mode of HIV Acquisition on HIV Survival in the Americas. AIDS Patient Care STDS 32:306-313
Carriquiry, Gabriela; Giganti, Mark J; Castilho, Jessica L et al. (2018) Virologic failure and mortality in older ART initiators in a multisite Latin American and Caribbean Cohort. J Int AIDS Soc 21:e25088
AIDS-defining Cancer Project Working Group of IeDEA, COHERE in EuroCoord (2018) Non-Hodgkin lymphoma risk in adults living with HIV across five continents. AIDS 32:2777-2786
Fink, Valeria I; Jenkins, Cathy A; Castilho, Jessica L et al. (2018) Survival after cancer diagnosis in a cohort of HIV-positive individuals in Latin America. Infect Agent Cancer 13:16
Grover, Surbhi; Desir, Fidel; Jing, Yuezhou et al. (2018) Reduced Cancer Survival Among Adults With HIV and AIDS-Defining Illnesses Despite No Difference in Cancer Stage at Diagnosis. J Acquir Immune Defic Syndr 79:421-429
Hughes, Rachael A; May, Margaret T; Tilling, Kate et al. (2018) Long terms trends in CD4+ cell counts, CD8+ cell counts, and the CD4+?: ?CD8+ ratio. AIDS 32:1361-1367
Caro-Vega, Y; Belaunzarán-Zamudio, P F; Crabtree-Ramírez, B et al. (2018) Trends in proportion of older HIV-infected people in care in Latin America and the Caribbean: a growing challenge. Epidemiol Infect 146:1308-1311
Shiels, Meredith S; Althoff, Keri N; Pfeiffer, Ruth M et al. (2017) HIV Infection, Immunosuppression, and Age at Diagnosis of Non-AIDS-Defining Cancers. Clin Infect Dis 64:468-475
AIDS-defining Cancer Project Working Group for IeDEA and COHERE in EuroCoord (2017) Comparison of Kaposi Sarcoma Risk in Human Immunodeficiency Virus-Positive Adults Across 5 Continents: A Multiregional Multicohort Study. Clin Infect Dis 65:1316-1326