The HIV Reservoir and Immune Landscape Across the Life Course of Women: Implications for Cure Strategies

Sex hormones and reproductive transitions profoundly shape immune, metabolic, neuropsychological, and mucosal biology, as well as HIV persistence, across women's lives. Although women constitute the majority of people with HIV worldwide, hormonal and reproductive biology are still not sufficiently incorporated into HIV cure research. Cisgender women, transgender women on gender-affirming hormone therapy (GAHT), and gender-diverse individuals assigned female at birth are underrepresented in cure studies, despite experiencing unique and changing hormonal states that influence estrogen signaling, tissue-specific hormone exposure, and immune function. Estradiol, progesterone, and hormone-based therapies, including contraception, GAHT, and menopausal hormone therapy, influence innate and adaptive immunity, inflammatory responses, epithelial barrier function, and cardiometabolic and neurocognitive pathways. These processes also shape tissue-specific HIV reservoir formation and maintenance, modulate proviral transcription, and affect immune effector functions. However, most HIV cure strategies have been developed without systematically considering these hormone-dependent mechanisms, which limits mechanistic understanding, broad applicability, and translational relevance. In this review, we synthesize emerging evidence at the intersection of reproductive endocrinology and HIV immunovirology, identify critical knowledge gaps, and propose priorities for life-course, hormone-informed HIV cure strategies. We argue that meaningful inclusion of women and gender-diverse individuals is essential not only for ethically grounded, equity-centered, community-engaged research practices but also for the scientific rigor needed to achieve durable ART-free virologic control and cure.