权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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（由申请人提供）：尽管广泛使用高效抗逆转录病毒疗法（HAART），但与 HIV 相关的神经认知障碍仍然非常常见。此外，越来越清楚的是，尽管有高效抗逆转录病毒疗法（HAART），艾滋病毒和密切相关的猿猴免疫缺陷病毒（SIV）仍然存在于大脑“避难所”中，而在大脑“避难所”中，有效的抗逆转录病毒药物的获取受到限制。然而，尽管HAART，在大脑中建立和维持HIV感染的机制在很大程度上还是未知的。该提案的总体目标是探索长寿命脑血管周围巨噬细胞 (PVM) 作为中枢神经系统 SIV 感染的靶细胞在初始病毒血症高峰期间的作用以及作为 SIV 的主要储存库的作用。 HAART 存在下的慢性感染期间的病毒。在我们之前的研究中，我们证明单核细胞周转率可以预测艾滋病的发病，并且与 SIV 猕猴模型中 SIV 脑炎的严重程度相关。最近，我们首次报道了鞘内注射脂质体封装的双膦酸盐可消除 SIV 感染的猕猴的脑部 PVM。我们的中心假设是，尽管进行了HAART，但PVM的HIV感染仍会导致持续性脑部感染和炎症，并且与代表组织巨噬细胞全身感染的血液单核细胞周转增加相关。第一个目标将确定是否消除急性感染中 CD4 T 细胞的可用性和感染是否会影响 PVM 的从头感染，以及在急性感染高峰期后消除 PVM 是否会降低大脑中的 DNA 前病毒载量。第二个目标是确定在单核细胞周转率增加到感染前基线水平以上后开始抗逆转录病毒治疗（ART）是否会影响 PVM 感染以及大脑和脑脊液病毒载量。第三个目标将侧重于在接受 ART 治疗的慢性感染的情况下消除 PVM。本申请中提出的研究具有创新性，因为它代表了与当前维持 HIV 感染患者病毒抑制的方法完全不同的新颖之处。我们在这里的贡献将是重要的，因为这是开发针对病毒感染的 PVM 或抑制 PVM 病毒感染的治疗策略的第一步。一旦这些策略可用，就有希望从大脑和其他组织中根除持续存在的艾滋病毒储存库。