Targeting Brain Macrophage Reservoirs of SIV during HAART

 描述(由申请人提供)：尽管高效抗逆转录病毒疗法(HAART)被广泛使用，但艾滋病毒相关的神经认知障碍仍然令人惊讶地普遍。此外，越来越明显的是，尽管进行了HAART，但艾滋病毒和与之密切相关的猿猴免疫缺陷病毒(SIV)仍然存在于大脑的“避难所”，在那里，原本有效的抗逆转录病毒药物的获取是有限的。然而，尽管进行了HAART，但在大脑中建立和维持艾滋病毒感染的机制在很大程度上是未知的。这项建议的总体目标是探讨长寿脑血管周围巨噬细胞(Pvm)作为SIV感染的靶细胞在最初的病毒血症高峰期作为中枢神经系统SIV感染的作用以及作为主要的病毒储存库的作用。 病毒在HAART存在的情况下慢性感染。在我们以前的研究中，我们在SIV猕猴模型中证明了单核细胞周转率预测艾滋病的发生，并与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包裹的双膦酸脂对感染SIV的猕猴脑室旁核的耗竭。我们的中心假设是，尽管HAART，但HIV感染PVM可导致持续性脑感染和炎症，并与代表组织巨噬细胞全身性感染的单核细胞周转增加有关。第一个目标将确定是否在急性感染中消除CD4T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后耗尽PVM是否会降低脑内的DNA前病毒负荷。第二个目标将确定单核细胞周转率高于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。 第三个目标将集中在抗逆转录病毒药物治疗慢性感染的背景下消融PVM。这项申请中提出的研究是创新的，因为它代表了与目前在艾滋病毒感染患者中保持病毒抑制的方法完全不同的一种全新方法。我们在这里的贡献将是重大的，因为这是开发针对病毒感染的PVM或抑制PVM的病毒感染的治疗策略的第一步。一旦这种策略可用，就有可能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.