HIV Theranostic

HIV治疗诊断

基本信息

批准号：
10198710
负责人：
Prasanta Kumar Dash
金额：
$ 68.53万
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：
2019
资助国家：
美国
起止时间：
2019-09-23 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10198710
关键词：
AIDS/HIV problem Active Sites Affect Anatomy Animals Anti-Retroviral Agents Antiviral Agents Area Attenuated Biodistribution Birth Bismuth Brain CD34 gene CD4 Positive T Lymphocytes Cell Count Cells Chemistry Clinical Cobalt Coin Confocal Microscopy Cytomegalovirus DNA Dendritic Cells Detection Diagnostic Drug Delivery Systems Drug Kinetics Drug Targeting Drug or chemical Tissue Distribution Effectiveness Engineering Evaluation Flow Cytometry Fluorescence Formulation Future Goals Grant Growth HIV HIV Infections HIV-1 Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Histologic Human Human immunodeficiency virus test Image Immune response Immunologist Inductively Coupled Plasma Mass Spectrometry Iron Label Laboratories Latent virus infection phase Lymphoid Lymphoid Tissue Magnetic Resonance Magnetic Resonance Imaging Magnetism Measurement Measures Metals Microglia Mononuclear Mus Nervous system structure Neuraxis Organelles Outcome Penetrance Peripheral Phagocytes Pharmaceutical Preparations Pharmacodynamics Phase Physiological Polymerase Chain Reaction Population Property Radioactivity Radiolabeled Regimen Reporting Research Resolution Rest Secure Shapes Signal Transduction Site Stains Structure Sulfur Surface System Technology Testing Therapeutic Tissues Viral Viral Load result Viral reservoir Virion Virus Virus Diseases Virus Latency Virus-like particle abacavir antiretroviral therapy base bioimaging brain tissue chemical property cytotoxicity detector digital expectation experimental study humanized mouse improved insight integrin alpha4beta7 lymph nodes macrophage monocyte mouse model multimodality nanoparticle nanorod nanosystems neuroAIDS novel particle pharmacokinetics and pharmacodynamics physical property pre-exposure prophylaxis radiologist reconstitution response single photon emission computed tomography targeted delivery theranostics trafficking uptake virology

项目摘要

Abstract Our laboratories birthed the field of human immunodeficiency virus (HIV) theranostics. The new field allows simultaneous detection (diagnostics) and treatment (therapeutic) for the identification and ultimate elimination of viral tissue compartments and cellular reservoir sites with a focus on the central nervous system. By employing theranostics viral entry sites in lymph nodes, gut and brain can be tracked during antiretroviral therapy (ART). Cellular viral targets including CD4+ T cell populations and mononuclear phagocytes (MP; monocytes, macrophages, microglia and dendritic cells) subcellular endosomal structures can now be targeted for drug delivery in sites of active viral growth. The advantage of theranostics rests in that any steps towards improved HIV therapeutics and elimination strategies that requires precise targeted delivery of antiviral drugs. Bringing virus-combating agents to anatomically privileged tissues of latent viral infection can be defined through magnetic resonance and single photon emission computed tomography imaging facilitated by multimodal antiretroviral drug (ARV) probes. To deploy such technologies, as virus detectors we have successfully mirrored HIV infection in both the human brain and in lymphoid tissue by creating a first in kind completely humanized “microglial” mouse. The animal is populated by human CD4+ T cells and MPs and as such contains the principal “human” HIV-1 target cells in a murine model background. Thus, in the current proposal we plan to advance a theranostic nanosystem through improvements in the physical and chemical properties of particles that resemble a complete HIV-1 virion. The realization of the projects’ goals can result in the accurate assessment of viral biodistribution and optimal antiretroviral responses. To achieve this outcome we will employ two different nanoparticle formats. The first is bismuth sulfur nanorods and the second is a pseudovirus. Each of the made particles will be detector-tagged and ARV loaded. The combinations of a bioimaging detector and payload deliverer defines our multimodality system that enables unique insights into virus compartmentalization, drug biodistribution and hidden viral reservoirs. The long-term goal is to improve current therapeutic regimens with an emphasis on those that target the nervous system. The research brings together a group of chemists, biologists, pharmacologists, virologists, radiologists and immunologists with a long successful track record of working effectively as a team with singular goals to develop products that facilitate HIV-1 control.

抽象的我们的实验室诞生了人类免疫缺陷病毒（HIV）治疗诊断学领域。同时检测（诊断）和治疗（治疗）以识别和最终消除病毒组织区室和细胞储存库位点，重点关注中枢神经系统。治疗诊断学可以在抗逆转录病毒治疗 (ART) 期间追踪淋巴结、肠道和大脑中的病毒进入位点。细胞病毒靶标包括 CD4+ T 细胞群和单核吞噬细胞（MP；单核细胞，巨噬细胞、小胶质细胞和树突状细胞）亚细胞内体结构现在可以作为药物的靶点治疗诊断学的优点在于可以改善病毒生长的任何步骤。 HIV 治疗和消除策略需要精确靶向递送抗病毒药物。可以通过磁性来定义潜伏病毒感染的解剖学上特殊组织的抗病毒剂多模式抗逆转录病毒促进共振和单光子发射计算机断层扫描成像为了部署此类技术作为病毒检测器，我们已经成功地镜像了艾滋病毒。通过创造第一个完全人性化的同类，在人脑和淋巴组织中感染 “小胶质细胞”小鼠由人类 CD4+ T 细胞和 MP 组成，因此含有因此，在当前的提案中，我们计划通过改善颗粒的物理和化学性质来推进治疗诊断纳米系统类似于完整的 HIV-1 病毒粒子项目目标的实现可以产生准确的结果。为了实现这一结果，我们将采用病毒生物分布和最佳抗逆转录病毒反应的评估。两种不同的纳米颗粒形式，第一种是硫铋纳米棒，第二种是假病毒。制成的颗粒将被贴上检测器标签并加载抗逆转录病毒药物。有效负载传送器定义了我们的多模态系统，该系统能够对病毒划分提供独特的见解，药物生物分布和隐藏病毒库的长期目标是改善当前的治疗方案。这项研究聚集了一群化学家，重点关注那些针对神经系统的研究。生物学家、药理学家、病毒学家、放射学家和免疫学家，在以下方面拥有长期成功的记录作为一个具有单一目标的团队有效地合作，开发促进 HIV-1 控制的产品。