Effects of Human Galectin-9 on the CNS HIV Reservoir

项目总结 而抗逆转录病毒疗法(Art)的出现大大降低了发病率和死亡率。 与艾滋病毒感染相关的是，由于潜伏感染细胞的持久性，无法根除病毒 在治疗过程中。越来越多的数据表明，艾滋病毒感染者通常会经历持久的免疫 即使在ART介导的病毒环境中，调节失调、慢性炎症和加速衰老也是如此 压制。这些现实使人们对制定根除艾滋病毒的战略产生了明显的兴趣 被感染的人。大量数据表明，中枢神经系统(CNS)是一个重要的解剖学部位 支持艾滋病毒在抗逆转录病毒治疗期间的持久性，可能是由于中枢神经系统和 许多抗逆转录病毒药物穿过血脑屏障的效果不佳。因此，它势在必行。 在中枢神经系统内部对新出现的艾滋病毒根除战略进行全面审查。 我们的团队最近证明了人类免疫调节碳水化合物结合蛋白 “Galectin-9”(Galectin-9)是HIV感染者抑制ART中HIV持续存在的决定因素。 Gal-9通过信号通路在体外有效地重新激活血源性CD4+T细胞中的潜伏HIV 通过细胞表面的特定糖链来调节调节HIV转录的关键宿主因子。 此外，Gal-9诱导APOBEC3宿主限制因子对HIV基因组进行致命性突变， 减弱病毒的传染性，并最大限度地减少艾滋病毒储存库在以下情况下被补充的可能性 潜伏期在治疗上是颠倒的。这些数据表明，Gal-9可能是耐久的基础 病毒学控制和新的治疗方法，包括“电击并杀死”艾滋病毒根除框架。 大量公布的数据描述了人类Gal-9在中枢神经系统生物学中的非常重要的作用，尽管 与中枢神经系统艾滋病毒持久性的相关性尚不清楚。在这个R01项目中，我们将评估 外源性Galectin-9在中枢神经系统隔室实现潜在的病毒重新激活和病毒清除，以及 阐明内源性Galectin-9在中枢神经系统HIV持续中的作用。在目标1中，我们将评估 重组半乳糖凝集素-9(rGal-9)对建立和逆转HIV在中枢神经系统潜伏期的作用 EDGE双报告病毒构建和小胶质细胞潜伏期模型。在目标2中，我们将确定是否 RGal-9给药在中枢神经系统启动抗病毒状态，促进持续的病毒学控制， 表征对细胞内在宿主限制机制和抗病毒细胞因子分泌的影响。在《目标3》中， 我们将确定脑脊液和脑组织中内源性Gal-9的表达水平是否相关 利用加州大学旧金山分校独特的艾滋病毒和心脏性猝死队列，CNS的艾滋病毒储存库规模很大。 这项研究将对Gal-9和细胞表面依赖于多糖的信号如何可能产生有价值的见解 利用它在中枢神经系统隔间实现病毒清除，这是寻找艾滋病毒治愈方法的关键一步。

PROJECT SUMMARY While the advent of antiretroviral therapy (ART) has dramatically reduced the morbidity and mortality associated with HIV infection, viral eradication is not achievable due to the persistence of latently-infected cells during treatment. Accumulating data suggest that HIV-infected individuals often experience persistent immune dysregulation, chronic inflammation, and accelerated aging even in the setting of ART-mediated viral suppression. These realities have created a pronounced interest in developing strategies to eradicate HIV in infected individuals. Ample data suggest that the central nervous system (CNS) is a critical anatomical site supporting HIV persistence during ART, likely due to the immune privileged nature of the CNS and the suboptimal penetration of many antiretroviral drugs across the blood-brain barrier. Therefore, it is imperative that emerging HIV eradication strategies are comprehensively examined within the CNS compartment. Our group has recently demonstrated that the human immunomodulatory carbohydrate-binding protein “galectin-9” (Gal-9) is a determinant of HIV persistence in HIV-infected individuals on suppressive ART. Administration of Gal-9 potently reactivates latent HIV in blood-derived CD4+ T cells ex vivo, by signaling through specific glycans on the cell surface to modulate key host factors that regulate HIV transcription. Furthermore, Gal-9 induces the APOBEC3 host restriction factors which lethally mutagenize the HIV genome, attenuating viral infectivity and minimizing the probability that the HIV reservoir will be replenished when latency is reversed therapeutically. These data suggest that Gal-9 may serve as a foundation for durable virologic control and novel curative approaches, including the “shock-and-kill” HIV eradication framework. Extensive published data describe a highly important role of human Gal-9 in the biology of the CNS, although relevance to CNS HIV persistence is as yet unknown. In this R01 project, we will evaluate the capacity of exogenous galectin-9 to achieve latent viral reactivation and viral clearance in the CNS compartment, and elucidate the role of endogenous galectin-9 in CNS HIV persistence. In Aim 1, we will evaluate the effects of recombinant galectin-9 (rGal-9) on the establishment and reversal of HIV latency in the CNS using a cutting- edge dual-reporter virus construct and microglial latency model, respectively. In Aim 2, we will determine if rGal-9 administration initiates an antiviral state in the CNS that promotes sustained virologic control, characterizing effects on cell-intrinsic host restriction mechanisms and antiviral cytokine secretion. In Aim 3, we will determine if endogenous Gal-9 expression levels in cerebrospinal fluid and brain tissue are associated with HIV reservoir size in the CNS, leveraging a unique HIV and Sudden Cardiac Death cohort at UCSF. This study will yield valuable insights into how Gal-9 and glycan-dependent signaling at the cell surface may be exploited to achieve viral clearance in the CNS compartment, a critical step in the search for an HIV cure.