Effects of Human Galectin-9 on the CNS HIV Reservoir

人半乳糖凝集素 9 对中枢神经系统 HIV 病毒库的影响

• 批准号: 9271836
• 负责人: Lishomwa C Ndhlovu
• 金额: $ 40.5万
• 依托单位: VITALANT
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-22 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9271836
• 关键词: APOCEC3G gene; Aging; Anti-Retroviral Agents; Antiviral Agents; Attenuated; Binding; Biological Assay; Biological Markers; Biology; Blood; Blood - brain barrier anatomy; Brain; CCL2 gene; CD28 gene; CD3 Antigens; CD4 Positive T Lymphocytes; Cell model; Cell surface; Cells; Cerebrospinal Fluid; Chronic; DNA; Data; Deaminase; Dimethyl Sulfoxide; Enzyme-Linked Immunosorbent Assay; Fluorescence; Foundations; Galactose Binding Lectin; Galactosides; Genetic Transcription; Goals; HIV; HIV Genome; HIV Infections; Hawaii; Human; Immune; Immunohistochemistry; Immunologic Surveillance; Individual; Inflammation; Integration Host Factors; Interleukin-1 beta; Interleukin-6; Latent Virus; Lectin; Measurement; Measures; Mediating; Messenger RNA; Microglia; Modeling; Morbidity - disease rate; Myeloid Cells; Nature; Neopterin; Neuraxis; Neuronal Injury; Pattern; Penetration; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Polysaccharides; Predisposition; Probability; Production; Proteins; Publishing; RNA; Recombinants; Reporter; Role; Sampling; Shock; Signal Transduction; Site; Universities; Viral; Virion; Virus; Virus Latency; antiretroviral therapy; brain tissue; carbohydrate binding protein; cohort; cytokine; experience; insight; interest; killings; monocyte; mortality; novel; novel strategies; peripheral blood; sudden cardiac death; sugar; tool; transcriptome sequencing

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.

项目概要 虽然抗逆转录病毒疗法（ART）的出现大大降低了发病率和死亡率 与 HIV 感染相关，由于潜伏感染细胞的持续存在，病毒无法根除 越来越多的数据表明，艾滋病毒感染者通常会经历持续的免疫。 即使在 ART 介导的病毒环境中，也会出现调节失调、慢性炎症和加速衰老的情况 这些现实引起了人们对制定根除艾滋病毒战略的浓厚兴趣。 大量数据表明，中枢神经系统（CNS）是一个关键的解剖部位。 支持抗逆转录病毒疗法期间艾滋病毒的持续存在，这可能是由于中枢神经系统和免疫系统的免疫特权性质 许多抗逆转录病毒药物穿过血脑屏障的渗透性不佳，因此，势在必行。 新兴的艾滋病毒根除策略在中枢神经系统内得到全面检查。 我们的研究小组最近证明，人类免疫调节碳水化合物结合蛋白 “半乳糖凝集素-9”（Gal-9）是接受抑制性 ART 治疗的 HIV 感染者中 HIV 持续存在的决定因素。 Gal-9 的给药可通过信号传导有效地重新激活体外血液来源的 CD4+ T 细胞中的潜伏 HIV 通过细胞表面的特定聚糖来调节调节HIV转录的关键宿主因子。 此外，Gal-9 诱导 APOBEC3 宿主限制因子，从而致命地诱变 HIV 基因组， 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得到补充的可能性 这些数据表明 Gal-9 可以作为持久性的基础。 病毒学控制和新的治疗方法，包括“休克和杀死”艾滋病毒根除框架。 大量已发表的数据描述了人类 Gal-9 在 CNS 生物学中的非常重要的作用，尽管 与 CNS HIV 持续存在的相关性尚不清楚。在这个 R01 项目中，我们将评估其能力。 外源半乳糖凝集素 9 可实现中枢神经系统区室中潜伏病毒的重新激活和病毒清除，以及 阐明内源性半乳糖凝集素 9 在 CNS HIV 持续存在中的作用 在目标 1 中，我们将评估其作用。 重组半乳糖凝集素 9 (rGal-9) 对中枢神经系统中 HIV 潜伏期的建立和逆转的影响 在目标 2 中，我们将分别确定边缘双报告病毒构建体和小胶质细胞潜伏期模型。 rGal-9 给药会在中枢神经系统中启动抗病毒状态，从而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。 我们将确定脑脊液和脑组织中的内源性 Gal-9 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源性猝死队列，了解中枢神经系统中艾滋病毒储存库的大小。 这项研究将为细胞表面 Gal-9 和聚糖依赖性信号传导如何发挥作用提供有价值的见解。 利用它来实现中枢神经系统隔室中的病毒清除，这是寻找艾滋病毒治疗方法的关键一步。