Elucidating and targeting t cell senescence-driven immune dysfunction in aging and HIV - t cell senescence is a state of stable cell cycle arrest driven by telomere shortening and DNA damage which…

The National Institute on Aging awarded the University of Miami $164,766 on September 5, 2026, under the Aging Research program (CFDA 93.866) to conduct research on T cell senescence-driven immune dysfunction in aging and HIV.

The research will establish a complete T cell senescence-associated secretory phenotype (SASP) atlas using fluorescence-activated cell sorting and mass spectrometry, then evaluate plasma biomarkers of T cell senescence during physiologic aging and in people with HIV. The project will assess relationships between T cell senescence and immune dysfunction and test interventions to improve immune responses in older age and aging populations. The work is based on observations of premature T cell senescence and suboptimal immune function in people with HIV despite virologic suppression, alongside hypotheses that senolytic therapy—which clears senescent T cells—could reduce inflammation, improve immune function, and enhance quality of life.

Performance occurs in Miami, Florida, with a period extending through March 31, 2030. This is a Project Grant, classified as an assistance award to a research institution rather than a procurement contract.

Elucidating and targeting t cell senescence-driven immune dysfunction in aging and HIV - t cell senescence is a state of stable cell cycle arrest driven by telomere shortening and DNA damage which is associated with aging. Senescent t cells secrete an array of soluble proteins known as the senescence- associated secretory phenotype (sasp). The accumulation of senescent t cells is hypothesized to drive aging- associated functional decline, inflammaging, and immune impairment. Our group has observed premature t cell senescence and suboptimal immune function in people with HIV (PWH) despite excellent art-induced virologic suppression. Chronic persistent immune activation from the HIV-1 reservoir is proposed to drive t cell senescence in PWH. We have observed a negative correlation between the frequency of senescent-like t cells and serologic flu vaccine responses, leading US to hypothesize that senescent t cells are linked to adaptive immune decline. A higher prevalence and earlier onset of multiple aging-associated conditions has been observed among PWH, which may be driven by premature t cell senescence. Application of senolytic therapy to clear senescent t cells is a promising strategy to reduce inflammation and immune decline and improve quality of life, which is of critical importance given the rapid demographic aging of the general population and PWH. Aim 1 will determine the complete t cell sasp atlas using fluorescence-activated cell sorting and mass spectrometry. Using highly sensitive multiplex immunoassays, comprehensive knowledge of the t cell sasp will be harnessed to evaluate plasma biomarkers of t cell senescence during physiologic aging and aging with HIV. This aim will provide broad insight into senescent t cell biology and inform the discovery of a t cell sasp-derived immune aging signature. Aim 2 will evaluate the relationship between t cell senescence and immune dysfunction and test interventions to improve immune responses in older age and in aging PWH. This aim will harness high-throughput functional immunology techniques such as spectral flow cytometry, CO-culture, and transcriptomics to mechanistically test the effects of aging and HIV on t cell senescence and elucidate the relationship between senescent t cells and cellular and serologic responses to flu vaccination. The findings of aim 1 will be integrated with those of aim 2 to provide a clear role for how senescent t cells and the t cell sasp regulate adaptive immune function. The main objective of this fellowship research is to functionally interrogate how senescent t cells influence adaptive immune responses in the context of aging with and without HIV and to aid in the therapeutic application of senolytic drugs to reduce senescent t cell burden to reduce inflammation and immune decline. Completion of this project will provide knowledge and training necessary to build an independent physician-scientist career which integrates areas of immunology, geroscience, and HIV.