IN VIVO DEPLETION OF CD16+ MONOCYTES IN SIV INFECTED MACAQUES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 通过似乎有效的抗逆转录病毒治疗，艾滋病毒感染者血浆中无法检测到的病毒水平可以实现。然而，由于不耐受或不顺从而终止治疗的患者，病毒负担会迅速卷土重来，这突显了病毒隐藏和持续存在的宿主的作用。一个这样的细胞库是单核/巨噬细胞系细胞。感染的单核细胞运输到组织并成为巨噬细胞，巨噬细胞是脑、心脏和肾脏等非淋巴器官感染的主要细胞类型。表达CD16抗原的血单核细胞亚群在感染HIV的人和感染SIV的猕猴中扩张，并优先携带病毒。CD16+单核细胞的感染和转运在HIV感染相关神经功能障碍的发病机制中起关键作用。然而，为了直接证明它们的致病作用，需要耗尽这些细胞。因此，我们建议使用SIV/猕猴神经艾滋病模型(感染SIV的恒河猴，CD8淋巴细胞耗尽)，使用一种抗体杀死CD16+单核细胞，从而阻断它们向组织的运输。在使用这个动物模型之前，我们发现CD16+单核细胞在初次感染和进展到艾滋病期间的双相扩张与脑神经元损伤相关。本项目的主要目的是确定CD16+单核细胞去除对HIV引起的脑部疾病和巨噬细胞中病毒感染的影响。抗CD16抗体治疗如果被发现有效，可以与现有的抗逆转录病毒方案结合使用，以消除艾滋病毒感染患者中残留的病毒库。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Undetectable levels of virus in the plasma of HIV infected patients can be achieved on seemingly effective antiretroviral therapy. However, patients that have terminated treatment, either because of intolerance or noncompliance, experience a rapid resurgence of viral burden, underscoring the role of reservoirs where the virus hide and persists. One such cellular reservoir is monocyte/macrophage lineage cells. Infected monocytes traffic to tissues and become macrophages, which are a major cell type infected in non-lymphoid organs such as the brain, heart and kidney. A subset of blood monocytes expressing the CD16 antigen expands in HIV infected humans and SIV infected macaques, and preferentially harbor virus. It has been hypothesized that the infection and traffic of CD16+ monocytes play a key role in the pathogenesis of neurologic dysfunction associated with HIV infection. For a direct demonstration of their pathogenic role, however, depletion of these cells will be required. Therefore, we propose to use a SIV/macaque model of neuroAIDS (rhesus monkeys that are SIV infected, CD8 lymphocyte depleted) with an antibody that kills CD16+ monocytes and therefore would block their traffic to tissues. Previously using this animal model, we found that biphasic expansion of CD16+ monocytes during primary infection and during progression to AIDS correlates with brain neuronal injury. The main objective of this project is to determine the effects of CD16+ monocyte depletion on HIV induced brain disease and virus infection in macrophages. Anti-CD16 antibody treatment, if found effective, could be used in combination with the existing antiretroviral regimen to eliminate residual viral reservoirs in HIV infected patients.