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HIV-1DetectionandEliminationFrom 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：
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
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/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

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.

摘要