Targeting Brain Macrophage Reservoirs of SIV during HAART

HAART 期间针对 SIV 的脑巨噬细胞库

基本信息

批准号：
9302842
负责人：
Woong-Ki Kim
金额：
$ 81.66万
依托单位：
EASTERN VIRGINIA MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-25 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9302842
关键词：
Acquired Immunodeficiency Syndrome Acute Address Affect Aftercare Animals Anti-Retroviral Agents Antibodies Applications Grants Astrocytes Blood - brain barrier anatomy Brain Bypass CD4 Positive T Lymphocytes Cells Central Nervous System Infections Cerebrospinal Fluid Chronic Constitution DNA Encapsulated Encephalitis Funding Opportunities Goals HIV HIV Infections HIV-associated neurocognitive disorder Highly Active Antiretroviral Therapy Human Individual Infection Inflammation Link Liposomes Macaca Macaca mulatta Microglia Modeling Neuraxis Outcome Patients Penetration Peripheral Phase Primates Public Health RNA Reporting Research Role Route SIV Severities Site Support System Systemic infection Testing Time Tissues Viral Viral Load result Viral reservoir Viremia Virus Virus Diseases Work antiretroviral therapy base bisphosphonate brain cell cell type cellular targeting design improved in vivo innovation liposomal delivery macrophage monocyte novel novel strategies novel therapeutics prevent public health relevance therapeutic development viral DNA

项目摘要

DESCRIPTION (provided by applicant): Despite the widespread use of highly active antiretroviral therapy (HAART), HIV-associated neurocognitive disorders remain surprisingly common. 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 despite HAART are largely unknown. The overall goal of this proposal is to explore the role of long-lived brain perivascular macrophages (PVM) as the target cells for SIV infection in the central nervous system during the initial peak viremia and as a major reservoir of virus during chronic infection in the presence of HAART. 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 HIV infection of PVM contributes to persistent brain infection and inflammation despite HAART and correlates with increased turnover of blood monocytes representing systemic infection of tissue macrophages. The first aim will determine whether eliminating availability and infection of CD4 T cells in acute infection will affect de novo infection of PVM, and whether depletion of PVM in the post-peak phase of acute infection will decrease DNA proviral load in the brain. The second aim will determine whether initiating antiretroviral therapy (ART) after the monocyte turnover increases above pre- infection baseline levels will affect PVM infection, and brain and cerebrospinal fluid viral loads. The third aim will focus on ablating PVM in the setting of ART-treated chronic infection. 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 patients. 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仍然令人惊讶。此外，越来越清楚的是，尽管HAART，HIV和与密切相关的Simian免疫缺陷病毒（SIV）在大脑“庇护所”中持续存在，在此，其他潜在抗逆转录病毒的机会受到限制。但是，在大脑目的地HAART中建立和维持HIV感染的机制在很大程度上是未知的。该提案的总体目的是探索长寿命大脑周围巨噬细胞（PVM）作为初始峰值病毒血症中中枢神经系统中SIV感染的目标细胞的作用 HAART存在的慢性感染期间的病毒。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的HIV感染有助于持续的大脑感染和感染目的地HAART，并且与代表组织巨噬细胞全身感染的血液单核细胞的营业额增加有关。第一个目的将决定消除急性感染中CD4 T细胞的可用性和感染将影响PVM的从头感染，以及PVM在急性感染后峰值阶段的耗竭是否会降低大脑中的DNA临时负荷。第二个目标将决定单核细胞周转率在感染前基线水平以上的增加后是否启动抗逆转录病毒疗法（ART）会影响PVM感染，而大脑和脑脊液病毒载荷。第三个目标将集中于在艺术治疗的慢性感染的情况下消融PVM。在本应用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感染患者的病毒抑制。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病毒感染的理论策略发展的第一步。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。