Project Summary Data support a higher prevalence of co-morbidities and accentuated or accelerated aging in people living with HIV (PLWH), including a higher prevalence of frailty and physical disability. The potential role of clonal hematopoiesis (CH) --the proliferation of hematopoetic stem cells with acquired mutations that confer a competitive growth advantage-- in promoting inflammation and aging-related complications in PLWH is unknown. While the prevalence of CH in the general population increases with age and is a potential pre- malignant, pro-inflammatory state associated with cardiovascular disease and mortality, there is a major gap in our knowledge about the prevalence and impact of CH in PLWH compared to controls without HIV. In a mouse model, bacterial translocation across the gut barrier via compromised epithelial tight junctions of the gastrointestinal tract causes endotoxin-responsive expansion of CH clones via toll-like receptor dependent pathways. An analogous state of compromised intestinal integrity in chronic HIV infection may favor expansion/persistence of CH clones. Our overarching hypothesis is that CH is more prevalent in PLWH and contributes to accentuated/accelerated aging. We will use a multidisciplinary approach with correlative studies in humans to address the following aims: 1) Test for the elevated prevalence and quantity of CH in PLWH compared to matched controls without HIV; 2) Test for increased cognitive impairment, frailty, reduced physical function, and inflammaging biomarkers in the presence of CH. We will use data and archived specimens from 500 participants age 55 and older living with HIV and an equal number without HIV from the Multicenter AIDS Cohort Study-Women's Interagency HIV Study Combined Cohort Study. Controls without HIV will be matched on age, race, and ethnicity. We will use targeted exome sequencing to detect CH mutations in blood using >2% variant allele fraction as the threshold for CH detection as in our prior study in the general population. We will measure a circulating biomarker of inflammation (interleukin-6), intestinal integrity, and bacterial translocation from archived plasma specimens. Our novel, exploratory investigations will yield important data to inform the design of more definitive human studies aimed at understanding the pathogenesis of aging- related complications in PLWH and will enable future interventional studies.