Targeting Brain Macrophage Reservoirs of SIV during HAART

 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HIV相关的神经认知障碍仍然令人惊讶地常见。此外，越来越清楚的是，尽管有HAART，艾滋病毒和密切相关的猿免疫缺陷病毒（SIV）坚持在大脑的“避难所”，在那里获得其他有效的抗逆转录病毒药物是有限的。然而，尽管有HAART，在大脑中建立和维持HIV感染的机制在很大程度上是未知的。本提案的总体目标是探索长寿脑血管周围巨噬细胞（PVM）在最初病毒血症高峰期间作为SIV感染中枢神经系统的靶细胞的作用，以及作为SIV主要储存库的作用。 在HAART存在下慢性感染期间的病毒。在我们以前的研究中，我们证明了单核细胞更新预测艾滋病的发病，并与SIV猕猴模型中SIV脑炎的严重程度相关。最近，我们首次报道了用鞘内注射脂质体包裹的双膦酸盐对SIV感染的猕猴脑PVM的消耗。我们的中心假设是，HIV感染PVM导致持续性脑感染和炎症，尽管HAART，并与血液单核细胞的周转增加，代表组织巨噬细胞的全身感染。第一个目标将确定是否消除CD4 T细胞的可用性和感染在急性感染 会影响PVM的从头感染，以及急性感染高峰后阶段PVM的消耗是否会降低大脑中的DNA前病毒载量。第二个目标将确定在单核细胞更新增加超过感染前基线水平后开始抗逆转录病毒治疗（ART）是否会影响PVM感染以及脑和脑脊液病毒载量。 第三个目标将侧重于在ART治疗慢性感染的情况下消融PVM。这项申请中提出的研究是创新的，因为它代表了一种完全不同于目前维持HIV感染患者病毒抑制的方法的新方法。我们的贡献将是显著的，因为它是朝着靶向病毒感染的PVM或抑制病毒感染的PVM的治疗策略的发展的第一步。一旦这些策略成为可能，就有希望从大脑和其他组织中根除持久的艾滋病毒储存库。

 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.