Sex-at-birth, innate immunity, and HIV reservoir selection

PURPOSE OF REVIEW: Sex-at-birth influences innate antiviral immunity, but its contribution to the long-term HIV reservoir composition remains incompletely defined. We review recent evidence linking sex chromosome-associated and hormonal influences on innate immunity, particularly natural killer (NK) cells, with HIV persistence and reservoir selection. RECENT FINDINGS: During suppressive antiretroviral therapy (ART), women and men have similar total HIV DNA, but women have lower reservoir transcriptional activity. In a long-term ART cohort, females had lower proviral phylogenetic complexity, greater clonal representation of intact proviruses, and more intact proviruses in transcriptionally repressive chromatin. These features were associated with peripheral innate immune profiles, particularly NK-cell receptor patterns. Women with HIV also showed stronger interferon-associated responses after Toll-like receptor 7 (TLR7) stimulation, whereas men produced more selected inflammatory cytokines. Additional studies implicate X-linked DDX3 in sex-associated plasmacytoid dendritic-cell interferon responses and support a role for NK-cell pressure in shaping persistence of the intact reservoir during ART. SUMMARY: Human data increasingly link sex-at-birth with both innate immune responsiveness and reservoir architecture, but do not establish causality. Longitudinal, tissue-informed studies with adequate representation of women and hormonal context are needed to determine whether these pathways shape reservoir selection and impact responses to immune-directed HIV cure strategies.