Estrogen depletion and immune activation and inflammation in women with HIV

As more women with HIV survive into older age, the menopausal transition has emerged as a critical yet underexplored determinant in HIV pathogenesis. Declining exposure to estrogens during menopause alters innate and adaptive immunity, driving inflammation, comorbidities, and viral persistence.

Estrogen influences both innate and adaptive immune responses. Estradiol enhances plasmacytoid dendritic cell type I interferon (IFN) production through Toll-like Receptor 7 (TLR7), promotes natural killer (NK) cell activity, and tempers monocyte/macrophage activation. Menopause reverses these effects, contributing to elevated inflammatory mediators. On the adaptive side, estrogen loss increases T-cell activation and exhaustion, impairs B-cell responses, and removes estrogen receptor (ER)-mediated suppression of HIV transcription. Together, these shifts may promote stabilization or expansion of the HIV reservoir in perimenopausal women with HIV, in contrast to the gradual decay often observed in men on antiretroviral therapy (ART).

Estrogen depletion during menopause reshapes immunity in women with HIV, fueling chronic inflammation, comorbidity risk, and HIV reservoir persistence. Integrating reproductive aging into HIV cure and comorbidity research, and testing hormone-based and anti-inflammatory interventions, will be essential to improve health outcomes for aging women with HIV.