Biological sex and age influence GS-9620 activity ex vivo

Toll-like receptors (TLRs) are being explored to enhance immunity in HIV cure strategies. The TLR7 agonist GS-9620 promotes immune activation, reactivates latent HIV, and delays viral rebound in some people with HIV. Previous work has shown that biological sex influences TLR7 signaling. This study examined the interplay between biological sex, age, and the sex hormones 17β-estradiol, progesterone, and testosterone on GS-9620's ability to promote cytokine secretion and activate CD4+ T, CD8+ T, and NK cells ex vivo. Interestingly, sex hormones had no effect on GS-9620-mediated immune activation or cytokine induction. However, we found that GS-9620 activity was influenced by age only in female donors. Further, we found that GS-9620-mediated CD4+ T cell activation was positively correlated with the induction of IFN-γ and IL-12, while CD4+ T cell activation and IL-12 production were negatively correlated with age. Additionally, CD8+ T cell activation was positively correlated with IFN-γ production. Mechanistically, IFN-γ was sufficient to promote higher immune activation of both CD4+ and CD8+ T cells in female versus male donors. In conclusion, biological sex and age, but not sex hormones, influence GS-9620-mediated immune activation. Understanding these factors will help in designing and evaluating future clinical trials using GS-9620 for an HIV cure.