The Impact of Biological Sex, Age, and Sex Hormones on the Activity of IL-15 and TLR Agonists for HIV Cure Strategies
Open Access DepositedHuman Immunodeficiency Virus (HIV)-1 is a retrovirus, which if left untreated, will lead to the development of acquired immunodeficiency syndrome (AIDS). There are an estimated 38 million people currently living with HIV (PWH), with younger women particularly, disproportionately affected. One of the main barriers to finding a cure for HIV are reservoirs of latently infected cells. These cells evade immune detection and have no known biomarkers to distinguish them from uninfected cells. While antiretroviral therapies (ART) halt infection, they cannot target this latent population, resulting in the need to find an effective cure for HIV. One HIV cure strategy that targets the latent reservoir, termed “shock and kill,” utilizes a Latency Reversing Agent (LRA) to activate latently infected cells. This leads to the transcription of new virus, which in turn leads to the consequent killing of the reactivated cells by either the immune system or by direct cytopathic effects from the virus. Several LRAs have reached clinical trials, including toll-like receptor (TLR) agonists and the γc-cytokine IL-15 superagonist N-803. In this work, we focus on LRAs that also promote immune activation to aid in the clearance of the latent reservoir, which is an important component toward ensuring the eradication of HIV infection. Currently, there is understudy of women and aging populations in HIV cure clinical trials. To achieve cure for PWH, sex and age differences must first be studied in basic and translational science. Our study examines the interplay that biological sex, chronological age, and sex hormones 17β-estradiol, progesterone, and testosterone may have on the activity of TLR7 agonist GS-9620 (aka Vesatolimod) and IL-15 within the context of “shock and kill” strategies. Additionally, we investigated the TLR3 and retinoic acid-inducible gene I (RIG-I) agonist polyinosinic-polycytidylic acid (Poly(I:C)) as an LRA coated on Prussian blue nanoparticles (PBNPs). Overall, our study found that biological sex and age, but not sex hormones, may influence GS-9620 and IL-15 activity. Further, Poly(I:C) coated PBNPs were effective as LRAs and immune-enhancing agents in both male and female donors. Interestingly, IL-15 mediated higher CD4 T cell activation in female donors compared to male donors. Additionally, a positive correlation between age with both IL-15-mediated CD8 T cell activation and IFN-γ production was observed. Furthermore, we found that the ability of GS-9620 to promote CD4 and CD8 T cell activation along with the induction of the pro-inflammatory cytokines IL-12, IFN-γ, and IL-1β were negatively correlated with age. Interestingly, this correlation was only found in female donors. Notably, sex hormones did not affect immune activation with either GS-9620 or IL-15, nor did they affect IL-15-mediated latency reversal in a primary cell model. Furthermore, 17β-estradiol and biological sex did not have a consistent impact on the reactivation of translation-competent reservoirs in CD4 T cells from ART-suppressed individuals living with HIV. Finally, Poly(I:C)-PBNPs demonstrated greater effectiveness in promoting immune activation in CD4 and CD8 T cells as well as HIV reactivation in a cell model of latency, compared to free Poly(I:C). No differences were observed between male and female donors. Overall, understanding how different biological variables such as biological sex, age, and sex hormones affect the activity of cure therapies will help us evaluate current and future clinical trials aimed toward HIV cure in diverse populations.
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Holmberg_gwu_0075A_16936.pdf | 2025-04-11 | Open Access |
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