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.

项目摘要 而抗逆转录病毒疗法（ART）的冒险大大降低了发病率和死亡率 与HIV感染相关，由于潜在感染的细胞的持续存在，无法实现病毒的根除 治疗期间。累积数据表明，感染HIV的个体通常会经历持续的免疫 即使在ART介导的病毒的情况下，甚至在ART介导的病毒的情况下，功能障碍，慢性炎症和加速衰老 抑制。这些现实引起了人们对制定放射性艾滋病毒的策略的明显兴趣 受感染的人。大量数据表明中枢神经系统（CNS）是关键的解剖部位 在艺术期间支持艾滋病毒的持久性，可能是由于中枢神经系统的免疫特权性质 许多抗逆转录病毒药物在血脑屏障中的次优渗透。因此，这是必须的 在中枢神经系统室内对新兴的艾滋病毒消除策略进行了全面研究。 我们的小组最近证明了人类免疫调节性碳水结合蛋白 “ Galectin-9”（GAL-9）是由HIV感染者对抑制性艺术的艾滋病毒持久性决定的。 通过信号传导，GAL-9的施用可能会在血液来源的CD4+ T细胞中重新激活潜在的CD4+ T细胞。 通过细胞表面上的特定聚糖调节调节HIV转录的关键宿主因子。 此外，GAL-9影响APOBEC3宿主限制因素，这些因素使HIV基因组诱变化，即 衰减病毒感染，并最大程度地减少艾滋病毒储存库的可能性 潜伏期被热逆转。这些数据表明GAL-9可能是耐用性的基础 病毒学控制和新颖的治疗方法，包括“冲击和杀死” HIV放射框架。 广泛发布的数据描述了人类GAL-9在中枢神经系统生物学中的重要作用，但是 与CNS HIV持久性的相关性尚不清楚。在这个R01项目中，我们将评估 外源性半乳糖素9以实现中枢神经系统室中的潜在病毒重新激活和病毒清除率，并且 阐明内源性乳糖素9在CNS HIV持久性中的作用。在AIM 1中，我们将评估 重组lectectin-9（RGAL-9）在中枢神经系统中使用刺激的艾滋病毒潜伏期的建立和逆转 边缘双重旋转病毒构建体和小胶质潜伏期模型。在AIM 2中，我们将确定是否 RGAL-9给药在中枢神经系统中启动抗病毒状态，以促进持续的病毒学控制， 表征对细胞中性宿主限制机制和抗病毒细胞因子分泌的影响。在AIM 3中， 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 中枢神经系统中的艾滋病毒储量大小，利用UCSF的独特艾滋病毒和突然的心脏死亡队列。 这项研究将对细胞表面的GAL-9和聚糖依赖性信号传导的宝贵见解可能为 被利用以在中枢神经系统隔室中实现病毒清除率，这是寻找HIV治疗的关键步骤。