HIV-1 Detection and Elimination From CNS Mononuclear Phagocytes

CNS 单核吞噬细胞中 HIV-1 的检测和消除

基本信息

批准号：
10327550
负责人：
Howard E Gendelman
金额：
$ 68.85万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10327550
关键词：
Affect Animal Model Animals Anti-Retroviral Agents Astrocytes Biochemical Biodistribution Biological Biology Birth Brain CD34 gene Cells Clustered Regularly Interspaced Short Palindromic Repeats Complex DNA Dendritic Cells Disease Evaluation Evolution Excision Formulation Foundations Genes Giant Cells Goals Growth Guide RNA HIV Hematopoietic Stem Cell Transplantation Homeostasis Human Hydrophobicity Immunologics Infection Knowledge Laboratories Link Longevity Lymphoid Lymphoid Tissue Mass Spectrum Analysis Methods Microglia Mind Molecular Molecular and Cellular Biology Mononuclear Mus Myelogenous Nebraska Neuraxis Nuclear Organ Pathway interactions Penetration Pericytes Peripheral Phagocytes Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Polymer Chemistry Predisposition Proteins RNA Radiolabeled Recycling Reporter Research Research Activity Rest Site Speed Spinal Sterilization Subcellular Fractions System Techniques Testing Therapeutic Therapeutic Intervention Tissues Variant Viral Viral reservoir Virus Virus Diseases Virus Replication Work animal imaging antiretroviral therapy base bioimaging blood-brain barrier function brain tissue design experimental study fluorophore gene therapy human disease human model humanized mouse immunoaffinity chromatography improved innovation late endosome lipid nanoparticle lipophilicity macrophage memory CD4 T lymphocyte monocyte mouse model nanocrystal nanoformulation nanoparticle neuroAIDS neurocognitive disorder novel novel therapeutics particle response self-renewal single-molecule FRET targeted delivery theranostics therapeutic evaluation therapeutic gene therapeutically effective trafficking transmission process viral rebound virology

项目摘要

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.

抽象的单核吞噬细胞（MP；单核细胞、巨噬细胞、树突状细胞和小胶质细胞）充当人类一型免疫缺陷病毒 (HIV-1) 储存库、病毒持续存在和潜伏的位点以及最终的诱导物器官疾病。所有这些通常都与 HIV-1 病理学有关。然而，MP 病毒的关键相关性病毒库存在于艾滋病毒感染者 (PLWH) 的中枢神经系统 (CNS) 中。在那些 PLWH 和接受抗逆转录病毒治疗 (ART)，中枢神经系统病毒的大小、范围和疾病相关性的证据水库的价值仍然被低估。实验室 MP 感染与组织持久性之间的不一致在受感染的人类宿主中的作用尚不清楚。 MP可以延长寿命并具有自我更新能力潜力，因此，与疾病的相关性可能比目前认为的更相关。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 的重要性自然感染。特别是对于中枢神经系统，HIV-1 在感染后不久就进入大脑并在血管周围巨噬细胞和 MGL 以及数量有限的星形胶质细胞。病毒设定点和 ART 时机启动决定了潜在储层的大小；每一个因素都会影响任何根除策略的效率。知识病毒动态、中枢神经系统病毒侵袭、MP 感染易感性以及中枢神经系统 HIV 病毒库的组成将促进有效的治疗干预。为了实现这些目标，我们将采用新颖的技术来研究实验室系统和新开发的人类小胶质细胞小鼠模型中的 MP HIV-1 储存库疾病。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消除亚细胞病毒感染的方法，细胞和组织水平上新设计的新颖治疗方法，包括基因治疗策略。我们的目标是确定天然和纳米制剂抑制病毒的效率（在亚细胞水平），根据病毒设定点（由启动定义）评估中枢神经系统病毒库的广度 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。