HIV-1 latency reversal and immune enhancing activity of IL-15 is not influenced by sex hormones.

The role of different biological variables including biological sex, age, and sex hormones in HIV cure approaches is not well understood. The γc-cytokine IL-15 is a clinically relevant cytokine that promotes immune activation and mediates HIV reactivation from latency. In this work, we examine the interplay that biological sex, age, and sex hormones 17β-estradiol, progesterone, and testosterone may have on the biological activity of IL-15. We found that IL-15-mediated CD4 T cell activation was higher in female donors compared to male donors. This difference was abrogated at high 17β-estradiol concentration. Additionally, there was a positive correlation between age and both IL-15-mediated CD8 T cell activation and IFN-γ production. In a primary cell model of latency, biological sex, age, or sex hormones did not influence the ability of IL-15 to reactivate latent HIV. Finally, 17β-estradiol did not consistently affect reactivation of translation-competent reservoirs in CD4 T cells from ART-suppressed people living with HIV. Our study has found that biological sex and age, but not sex hormones, may influence some of the biological activities of IL-15. Understanding how different biological variables affect the biological activity of cure therapies will help us evaluate current and future clinical trials aimed towards HIV cure in diverse populations.