HIV-1DetectionandEliminationFrom CNS Mononuclear Phagocytes

摘要 单核吞噬细胞（MP;单核细胞、巨噬细胞、树突细胞。和小胶质细胞）作为人类 免疫缺陷病毒1型（HIV-1）的储库，病毒持久性和潜伏期的位点，以及终末- 器官疾病所有这些都与HIV-1病理学有关。然而，MP病毒的关键相关性 艾滋病毒感染者（PLWH）的中枢神经系统（CNS）中有一个病毒库。在这些PLWH和 接受抗逆转录病毒治疗（ART），CNS病毒感染的大小，范围和疾病相关性的证据 水库仍在升值。实验室MP感染与组织持久性的不一致性 在受感染的人类宿主中也是未知的。MP具有延长寿命和自我更新能力 潜在的，因此，在疾病中可能比目前认识到的更相关。评价 一般来说，MP的重要性，特别是小胶质细胞将有助于定义MP在治疗过程中的重要性。 自然感染。对于中枢神经系统，HIV-1在感染后很快进入大脑，并在大脑中复制。 血管周围巨噬细胞和MGL沿着以及有限数量的星形胶质细胞。病毒设定点和ART时间 启动决定了潜在的水库规模;每一个影响任何根除战略的效率。知识 病毒动力学、CNS病毒侵袭、MP感染易感性和CNS HIV储库的组成 将促进有效的治疗干预。为了实现这些目标，我们将采用新的技术来研究 在实验室系统和新开发的人类小胶质细胞小鼠模型中， 疾病我们将使用基础和应用MP生物学，治疗诊断学，新型ART纳米制剂，分子和 细胞生物学，以及我们独特的动物模型来研究在亚细胞中消除病毒感染的方法， 细胞和组织水平与新设计的和新的治疗方法，包括基因治疗 战略布局我们的目的是确定天然和纳米制剂ART的病毒抑制效率（在 亚细胞水平），评估CNS病毒储库相对于病毒设定点的宽度（由启动 的ART），并探索在新开发的人源化小胶质细胞中消除HIV-1的组合策略。 老鼠.

ABSTRACT Mononuclear phagocytes (MP; monocytes, macrophages, dendritic cells. and microglia) serve as human immunodeficiency virus type one (HIV-1) reservoirs, sites of viral persistence and latency, and inducers of end- organ disease. All are commonly linked to HIV-1 pathobiology. However, the key relevance of the MP viral reservoir rests in the central nervous system (CNS) of those people living with HIV (PLWH). In those PLWH and receiving antiretroviral therapy (ART), the evidence for the size, scope, and disease relevance of the CNS viral reservoir remains under appreciated. The discordance between laboratory MP infection and tissue persistence in an infected human host is also not yet known. MP can have an extended life span and possess self-renewing potential, and as such, are likely more relevant in disease than currently appreciated. Evaluation of the significance of MPs, in general, and the microglia specifically will help define the importance of MPs during natural infection. For the CNS specifically, HIV-1 enters the brain soon after infection and replicates in perivascular macrophages and MGL along with limited numbers of astrocytes. Viral set point and timing of ART initiation determines the latent reservoir size; each affects the efficiency of any eradication strategy. Knowledge of the viral dynamics, CNS viral invasion, susceptibility to MP infection, and composition of CNS HIV reservoir will facilitate effective therapeutic interventions. To each of these ends, we will employ novel techniques to study the MP HIV-1 reservoir in laboratory systems and in a newly developed human microglial mouse model of human disease. We will use basic and applied MP biology, theranostics, novel ART nanoformulations, molecular and cellular biology, and our unique animal model to study the means to eliminate viral infection at the subcellular, cellular, and tissue level with newly designed and novel therapeutic methods that include gene therapy strategies. Our aims are to determine the efficiency of viral suppression by native and nanoformulated ART (at subcellular level), assess the breadth of the CNS viral reservoirs against viral set points (defined by the initiation of ART), and to explore combination strategies for HIV-1 elimination in a new developed humanized microglial mouse.