CD151 identifies a cytotoxic CD4 T cell population enriched in people with HIV that later develop cancer.

People with HIV (PWH) exhibit persistent immune activation despite effective antiretroviral therapy, contributing to risk of non-AIDS-associated comorbidities such as cancer. Cell populations reflecting immune remodeling trajectories preceding malignancy are poorly characterized. Using peripheral blood mononuclear cells from an adult cohort (25-65 yr), we quantified the tetraspanin CD151 on T cells in people without HIV (PWOH), PWH without documented cancer during follow-up, and PWH who subsequently developed a non-AIDS-defining cancer (PWHc), with samples collected a median of 5 yr prior to cancer diagnosis. In PWOH, CD4+CD151+ T cell frequencies increased with age, consistent with physiologic immune aging. In contrast, elevated CD4+CD151+ frequencies were observed at younger ages in both HIV-positive groups, with the typical age-associated increase attenuated. Notably, frequencies were highest in PWHc. CD151 expression was not associated with increased CD25 or CD69, indicating that expansion was not explained by generalized T cell activation. Instead, CD4+CD151+ T cells were enriched for granzyme B and localized predominantly to CD28- effector memory (CD45RA-CCR7-) compartments, consistent with a cytotoxic CD4+ (cCD4) phenotype. Single-cell RNA sequencing of 1 participant per group identified a cCD4+ transcriptional cluster enriched in the PWHc sample. Here, we report that CD151 identifies a cCD4 T cell lineage that accumulates with age in PWOH but appears prematurely expanded in virally suppressed PWH, particularly in PWHc. These findings support CD151+cCD4 T cell expansion as a feature of altered immune remodeling detectable years before cancer diagnosis, suggesting a potential role in mechanisms linking chronic immune dysregulation to malignancy risk in PWH.