Sex-modulated associations between cytomegalovirus cell-associated DNA and cognition in people with HIV on ART.

BACKGROUND: People with HIV (PWH) remain at risk for cognitive impairment, despite effective antiretroviral therapy (ART), a phenomenon linked to chronic immune activation and inflammation. Cytomegalovirus (CMV) has been implicated in HIV-associated neurocognitive impairment, but most studies rely on serologic measures that may not capture biologically relevant viral-host interactions. Few studies have examined cell-associated CMV markers or evaluated sex-specific associations with cognition. METHODS: We conducted a retrospective cross-sectional analysis of 485 PWH on suppressive ART (HIV RNA<200 copies/ml). Cognitive performance was assessed globally and across seven domains. Cell-associated CMV, Epstein-Barr virus (EBV), and HIV cell-associated DNA in peripheral blood mononuclear cells (PBMCs) were quantified by ddPCR, and CMV and EBV immunoglobulin G (IgG) levels were measured by ELISA. Multivariable linear regression models adjusted for demographic and clinical covariates were used to assess associations with cognitive performance, including evaluation of sex interactions, with false discovery rate correction applied. RESULTS: In adjusted models, lower cell-associated CMV DNA, but not CMV IgG, EBV markers, or HIV DNA, was associated with poorer working memory and global cognitive performance. Significant interactions between CMV DNA and sex were observed for global, executive function, processing speed, and memory. In sex-stratified analyses, these associations were present among women but not in men. CONCLUSIONS: Cell-associated CMV DNA demonstrates sex-modified associations with cognitive performance among ART-suppressed PWH, with effects observed primarily in women. These findings, based on cellular rather than serologic CMV measures, underscore the complexity of host-virus interactions and cautions against interpreting cell-associated CMV DNA as a simple proxy for pathogenic viral activity.