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

Abstract

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.