HIV Theranostic

HIV治疗诊断

• 批准号: 10439638
• 负责人: Prasanta Kumar Dash
• 金额: $ 68.46万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 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/10439638
• 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

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.

摘要 我们的实验室诞生了人类免疫缺陷病毒(HIV)基因治疗领域。新字段允许 同时检测(诊断)和治疗(治疗)以识别和最终消除 病毒组织隔间和细胞储存区，重点是中枢神经系统。通过雇用 在抗逆转录病毒治疗(ART)期间，可以追踪淋巴结、肠道和大脑中的Theranostics病毒进入部位。 细胞病毒靶标包括CD4+T细胞群和单核巨噬细胞(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 在病毒活跃生长的地点投放。治疗反流学的优势在于，任何朝着改进的步骤 艾滋病毒治疗和消除战略，需要精确地定向提供抗病毒药物。带来 潜伏病毒感染的解剖学特权组织的抗病毒药物可以通过磁力来定义 多模式抗逆转录病毒促进的共振和单光子发射计算机断层扫描成像 药物(ARV)探头。为了部署这样的技术，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人类感染人类大脑和淋巴组织 “小胶质”小鼠。这种动物由人类的CD4+T细胞和MPS组成，因此含有 在小鼠模型背景下的主要人类HIV-1靶细胞。因此，在目前的提案中，我们计划 通过改善粒子的物理和化学性质来推进医用纳米系统 就像一个完整的HIV-1病毒粒子。项目目标的实现可以导致准确的 评估病毒的生物分布和最佳抗逆转录病毒反应。为了实现这一结果，我们将采用 两种不同的纳米颗粒形式。第一种是铋硫纳米棒，第二种是假病毒。每一个 制造的颗粒将被贴上探测器标签并装载ARV。生物成像探测器和 有效载荷递送器定义了我们的多模式系统，该系统可以对病毒分区提供独特的见解， 药物的生物分布和隐藏的病毒库。长期目标是改进目前的治疗方案。 重点放在那些针对神经系统的基因上。这项研究汇集了一群化学家， 生物学家、药理学家、病毒学家、放射学家和免疫学家 作为一个团队有效地工作，具有单一的目标，开发促进HIV-1控制的产品。