HIV-1DetectionandEliminationFrom CNS Mononuclear Phagocytes

CNS 单核吞噬细胞中 HIV-1 的检测和消除

• 批准号: 10454408
• 负责人: Howard E Gendelman
• 金额: $ 69.08万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 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/10454408
• 关键词: Affect; Animal Model; 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; Interruption; 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; Persons; Phagocytes; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Polymer Chemistry; Predisposition; Proteins; RNA; Radiolabeled; Recycling; Reporter; Research; Research Activity; Rest; Site; Speed; Spinal Cord; Sterilization; Subcellular Fractions; System; Techniques; Testing; Therapeutic; Therapeutic Intervention; Tissues; Tropism; Variant; Viral; Viral reservoir; Virus; Virus Diseases; Virus Replication; Work; animal imaging; antiretroviral therapy; base; bioimaging; blood-brain barrier function; brain tissue; chronic infection; 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; treatment response; viral rebound; virology

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.

摘要 单核巨噬细胞(MP)；单核细胞、巨噬细胞、树突状细胞。和小胶质细胞)作为人类 免疫缺陷病毒1型(HIV-1)的贮存库、病毒持续和潜伏的部位以及终末病毒的诱导物 器官疾病。所有这些都与HIV-1病理生物学有关。然而，MP病毒的关键相关性 蓄水池位于艾滋病毒携带者的中枢神经系统(CNS)。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 储集层仍未得到充分重视。实验室MP感染与组织持久性的不一致性 在被感染的人类中，宿主也是未知的。MP可以延长寿命并具有自我更新能力 潜在的，因此，可能更相关的疾病比目前认识到的。对该计划的评估 一般说来，MPS的意义和小胶质细胞将特别有助于确定MPS在 自然感染。特别是对于中枢神经系统，HIV-1在感染后不久进入大脑，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。ART的病毒式设定点和时机 启动决定了潜在的储存库大小；每一项都影响到任何根除战略的效率。知识 病毒动态、中枢神经系统病毒侵袭、对MP感染的易感性以及中枢神经系统HIV储备库的组成 将促进有效的治疗干预。为了达到这些目的，我们将使用新的技术来研究 实验室系统和新开发的人类小胶质细胞模型中的MP HIV-1储存库 疾病。我们将使用基础和应用MP生物学、基因治疗学、新的ART纳米配方、分子和 细胞生物学，以及我们独特的动物模型，研究消除亚细胞病毒感染的方法， 细胞和组织水平的新设计和新的治疗方法，包括基因治疗 战略。我们的目标是确定天然和纳米配方ART抑制病毒的效率(在 亚细胞水平)，对照病毒设定点(由启动定义)评估CNS病毒库的广度 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。