Holmberg Carissa S, Levinger Callie, Ward Adam R, Bosque Alberto
Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC, USA.
Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.6.
JCI Insight. 2025 May 6;10(12). doi: 10.1172/jci.insight.182242. eCollection 2025 Jun 23.
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.
Toll样受体（TLRs）正在被探索用于增强HIV治愈策略中的免疫力。TLR7激动剂GS-9620可促进免疫激活，重新激活潜伏的HIV，并延缓一些HIV感染者的病毒反弹。先前的研究表明，生理性别会影响TLR7信号传导。本研究考察了生理性别、年龄以及性激素17β-雌二醇、孕酮和睾酮之间的相互作用对GS-9620在体外促进细胞因子分泌以及激活CD4+T细胞、CD8+T细胞和NK细胞能力的影响。有趣的是，性激素对GS-9620介导的免疫激活或细胞因子诱导没有影响。然而，我们发现GS-9620的活性仅在女性供体中受年龄影响。此外，我们发现GS-9620介导的CD4+T细胞激活与IFN-γ和IL-12的诱导呈正相关，而CD4+T细胞激活和IL-12产生与年龄呈负相关。另外，CD8+T细胞激活与IFN-γ产生呈正相关。从机制上讲，IFN-γ足以促进女性供体中CD4+和CD8+T细胞比男性供体具有更高的免疫激活。总之，生理性别和年龄而非性激素会影响GS-9620介导的免疫激活。了解这些因素将有助于设计和评估未来使用GS-9620进行HIV治愈的临床试验。
