Targeting Brain Macrophage Reservoirs of Infection in Pediatric NeuroAIDS

针对小儿神经艾滋病感染的脑巨噬细胞库

• 批准号: 8993090
• 负责人: Woong-Ki Kim
• 金额: $ 20.83万
• 依托单位: EASTERN VIRGINIA MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-26 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8993090
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adult; Affect; Animals; Applications Grants; Astrocytes; Blood - brain barrier anatomy; Brain; Cells; Central Nervous System Diseases; Central Nervous System Infections; Child; Childhood; Chronic; Development; Disease Progression; Drug Formulations; Early treatment; Encapsulated; Encephalitis; Goals; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Highly Active Antiretroviral Therapy; Human; Individual; Infant; Infection; Inflammation; Lead; Life; Link; Liposomes; Macaca; Macaca mulatta; Maintenance; Microglia; Modeling; Neonatal; Neuraxis; Newborn Infant; Outcome; Penetration; Public Health; RNA; Recruitment Activity; Reporting; Research; Role; SIV; Severities; Site; Source; Testing; Time; Tissues; Viral; Viral Load result; Virus; Virus Diseases; Work; antiretroviral therapy; base; bisphosphonate; brain size; cell type; cellular targeting; design; improved; in vivo; innovation; macrophage; monocyte; neonate; neuroAIDS; neuroinflammation; nonhuman primate; novel; novel strategies; novel therapeutics; public health relevance; reconstitution; therapeutic development; viral DNA

 DESCRIPTION (provided by applicant): Despite the widespread use of highly active antiretroviral therapy (HAART), HIV-associated neurocognitive disorders remain surprisingly common in both adults and children. Moreover, it is becoming clear that despite HAART, HIV and the closely-related simian immunodeficiency virus (SIV) persist in the brain 'sanctuary', where access of otherwise potent antiretrovirals is limited. However, the mechanisms that establish and maintain HIV infection in the brain during HAART are largely unknown. The overall goal of this proposal is to explore the role of long-lived brain perivascular macrophages (PVM) as a significant source of SIV infection and inflammation in the brain of SIV-infected infant macaques receiving suppressive antiretroviral therapy (ART). In our previous studies, we demonstrated that monocyte turnover predicts the onset of AIDS and is correlated with severity of SIV encephalitis in the SIV macaque model. Recently we have reported for the first time depletion of brain PVM in SIV-infected macaques with intrathecally administered liposome-encapsulated bisphosphonates. Our central hypothesis is that PVM are a significant source of persistent CNS infection and inflammation in HIV-infected newborns starting HAART with high monocyte turnover. The first aim will determine whether initiating ART after the monocyte turnover increases above pre-infection baseline levels will affect PVM infection and brain and CSF viral loads. The second aim will focus on ablating PVM in the setting of ART-treated chronic SIV infection. This study will result in better characterization of brain PVM (e.g., phenotypic markers, turnover and infection) that will help develop eradication therapy, tailored directly for the brain, and for targeting these cells selectively. The research proposed in this application is innovative because it represents an entirely novel departure from the current approach to maintaining viral suppression in HIV- infected children. Our contribution here will be significant because it is a first step toward the development of therapeutic strategies for targeting virus-infected PVM or inhibiting viral infection of PVM. Once such strategies become available, there is promise that persistent HIV reservoirs could be eradicated from brain and other tissues.

 描述（由适用提供）：尽管使用了高度活跃的抗逆转录病毒疗法（HAART），但与HIV相关的神经认知疾病在成人和儿童中仍然令人惊讶。此外，越来越明显的是，尽管HAART，HIV和密切相关的Simian免疫缺陷病毒（SIV）在大脑“庇护所”中持续存在，在此，其他潜在的抗逆转录病毒的机会受到限制。但是，在HAART期间，建立和维持大脑中HIV感染的机制在很大程度上尚不清楚。该提案的总体目标是探索长寿命的大脑周围巨噬细胞（PVM）作为SIV感染的SIV感染和感染的重要来源，该大脑接受了SIV感染的婴儿猕猴接受抑制性抗逆转录病毒疗法（ART）。在我们先前的研究中，我们证明了单核细胞周转率预测艾滋病的发作，并且与SIV猕猴模型中SIV脑炎的严重程度相关。最近，我们报道了脑PVM在SIV感染的猕猴中首次耗尽，并具有固定的脂质体封装的双膦酸盐。我们的中心假设是，PVM是HIV感染的新生儿中持续性中枢神经系统感染和感染的重要来源，起源于单核细胞更高的HAART。第一个目的将决定单核细胞周转率增加以上的启动ART是否会影响PVM感染，大脑和CSF病毒载荷。第二个目标将集中于在艺术治疗的慢性SIV感染的情况下消融PVM。这项研究将使脑PVM（例如表型标记，周转和感染）更好地表征，这将有助于开发根除治疗，直接针对大脑定制，并选择性地靶向这些细胞。该应用程序中提出的研究具有创新性，因为它代表了与当前的方法完全不同的方法来维持感染HIV感染的儿童的病毒抑制。我们在这里的贡献将是重要的，因为这是朝着靶向病毒感染PVM或抑制PVM病毒感染的热策略发展的第一步。一旦这种策略可用，就有保证可以将持续的HIV水库从大脑和其他组织中放大。