A new multi-center study led by investigators at the Yu Lab reports that biological sex influences how the body “selects” long-lived HIV reservoir cells during years of effective antiretroviral therapy. The team finds stronger innate immune pressure in females, offering fresh clues for cure-directed strategies.

Published in Science Translational Medicine, the study analyzed more than 4,000 individual HIV proviruses from 65 adults (30 females and 35 males) who had been on suppressive therapy for a median of 20 years. In many females, intact HIV tended to sit in quieter, harder-to-switch-on parts of the genome. In males, the intact virus more often appeared in typical genes and showed more limited signs of adapting to immune pressure.

The study also looked at the immune system’s first-line defenses. Females, especially those whose viral reservoirs were in quiet genomic regions, showed stronger signals from innate immune cells like dendritic cells and natural killer cells. This suggests that stronger immune pressure in females may push intact HIV into deeper latency, where the virus is harder to reactivate and less likely to fuel viral rebound if therapy is interrupted. This is consistent with the delayed viral rebound kinetics in females compared to males after ART treatment interruption.

Understanding these sex-linked patterns can guide cure strategies. If the virus is more often “silenced” in females, treatments that wake and clear silent virus may need to work differently than in males. The authors highlight the importance of including sex as a core variable when testing new approaches so that future cure studies are designed to work for everyone.

By illuminating how sex differences shape the hidden HIV reservoir, this work underscores the need to design and test cure strategies, especially innate immunity–based approaches, with sex as a core variable so that therapies are optimized for everyone affected by HIV.