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.

抽象的 我们的实验室孕育了人类免疫缺陷病毒（HIV）疗法的领域。新领域允许 简单检测（诊断）和治疗（治疗），以识别和最终消除 病毒组织室和细胞储存部位，重点是中枢神经系统。通过雇用 在抗逆转录病毒疗法（ART）期间，可以跟踪淋巴结，肠道和脑的疗法病毒进入部位。 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，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针对药物 在主动病毒生长的部位递送。激进的优势取决于进步的任何步骤 艾滋病毒疗法和消除策略需要精确靶向抗病毒药。带来 可以通过磁性定义与潜在病毒感染的解剖学特权组织一起进行病毒轰动的剂 通过多模式抗逆转录病毒制备的共振和单光子发射计算机断层扫描成像 药物（ARV）问题。为了部署此类技术，作为病毒探测器，我们成功地反映了HIV 通过创建一种完全人性化的第一个中的第一个，在人脑和淋巴组织中感染 “小胶质细”鼠标。该动物被人类CD4+ T细胞和MP填充，因此包含 在鼠模型背景下，主“人” HIV-1靶细胞。在当前的建议中，我们计划 通过改善颗粒的物理和化学特性来提高疗法纳米系统 这类似于完整的HIV-1病毒体。实现项目目标可以导致准确性 评估病毒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格式。第一个是苯硫硫纳米棒，第二个是假病毒。每个 制成的颗粒将被探测器标签并加载ARV。生物成像检测器和 有效载荷递送器定义了我们的多模式系统，该系统能够对病毒隔室化的独特见解， 药物生物分布和隐藏的病毒库。长期目标是改善当前的治疗方案 强调针对神经系统的人。该研究汇集了一群化学家， 生物学家，药理学家，病毒学家，放射科医生和免疫学家，他们的成功记录很长 作为一个具有奇异目标的团队有效工作，以开发促进HIV-1控制的产品。