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 抗逆转录病毒治疗（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， 在治疗期间。越来越多的数据表明，艾滋病毒感染者经常经历持续的免疫反应， 即使在ART介导的病毒感染的情况下， 镇压这些现实使人们对制定消除艾滋病毒的战略产生了明显的兴趣， 感染的人。大量数据表明，中枢神经系统（CNS）是一个关键的解剖部位 在ART期间支持HIV持续存在，可能是由于CNS的免疫特权性质和 许多抗逆转录病毒药物通过血脑屏障的渗透性不佳。因此，当务之急是 新出现的HIV根除策略在CNS隔室内得到全面检查。 我们的研究小组最近证明，人类免疫调节性碳水化合物结合蛋白 "半乳糖凝集素-9"（Gal-9）是在接受抑制性ART的HIV感染个体中HIV持续存在的决定因素。 Gal-9的给药通过信号传导在离体血液来源的CD4 + T细胞中有效地再活化潜伏的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，其致死性地诱变HIV基因组， 减弱病毒的传染性，并最大限度地减少HIV储存库被补充的可能性， 潜伏期在治疗上被逆转。这些数据表明，Gal-9可以作为持久的基础， 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R01项目中，我们将评估 外源性半乳糖凝集素-9以实现CNS区室中的潜伏病毒再活化和病毒清除，和 阐明内源性半乳糖凝集素-9在CNS HIV持久性中的作用。在目标1中，我们将评估 重组半乳糖凝集素-9（rGal-9）对使用切割- 边缘双报告病毒构建体和小胶质细胞潜伏期模型。在目标2中，我们将确定 rGal-9给药在CNS中引发抗病毒状态，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的内源性Gal-9表达水平是否与 利用UCSF独特的HIV和心源性猝死队列， 这项研究将产生有价值的见解如何半乳糖-9和聚糖依赖性信号在细胞表面可能是 用于实现CNS隔室中的病毒清除，这是寻求HIV治愈的关键步骤。