HIV Theranostic

HIV治疗诊断

• 批准号: 10677633
• 负责人: Prasanta Kumar Dash
• 金额: $ 68.38万
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677633
• 关键词: Acceleration; 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; Central Nervous System; 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; Endosomes; Engineering; Evaluation; Flow Cytometry; Fluorescence; Formulation; Future; Goals; Grant; Growth; HIV; HIV Infections; HIV-1; HIV/AIDS; 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; Macrophage; Magnetic Resonance; Magnetic Resonance Imaging; Magnetism; Measurement; Measures; Metals; Microglia; Mononuclear; Mus; Nervous System; Organelles; Outcome; Penetrance; Peripheral; Phagocytes; Pharmaceutical Preparations; Pharmacodynamics; Phase; Physiological; Polymerase Chain Reaction; Population; Predisposition; 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; bioimaging; brain tissue; chemical property; cytotoxicity; detector; digital; expectation; experimental study; humanized mouse; imaging detector; improved; insight; integrin alpha4beta7; lymph nodes; monocyte; mouse model; multimodality; nanoparticle; nanorod; nanosystems; neuroAIDS; novel; particle; pharmacokinetics and pharmacodynamics; physical property; pre-exposure prophylaxis; radiologist; reconstitution; response; screening; 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）治疗诊断学领域。新字段允许 同时检测（诊断）和治疗（治疗），以确定和最终消除 病毒组织隔室和细胞储库位点，重点是中枢神经系统。通过采用 在抗逆转录病毒治疗（ART）期间，可以追踪淋巴结、肠道和脑中的病毒进入位点。 细胞病毒靶标包括CD 4 + 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靶向药物 在活跃的病毒生长部位进行递送。治疗诊断学的优势在于，任何改善 HIV治疗和消除策略需要精确靶向递送抗病毒药物。带来 可以通过磁共振成像来确定对潜伏病毒感染的解剖学特权组织的抗病毒剂， 共振和单光子发射计算机断层扫描成像促进多模式抗逆转录病毒 药物（ARV）探针。为了部署这些技术，作为病毒检测器，我们成功地将艾滋病毒 通过创造第一种完全人源化的， “小胶质细胞”小鼠。该动物由人CD 4 + T细胞和MP构成，因此含有 主要的“人”HIV-1靶细胞在鼠模型背景。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治疗诊断纳米系统 类似于一个完整的HIV-1病毒体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。为了实现这一目标，我们将 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。中的每 所制造的粒子将被检测器标记并装载ARV。生物成像检测器和 payload deliverer定义了我们的多模态系统，该系统能够对病毒区室化进行独特的见解， 药物生物分布和隐藏的病毒库。长期目标是改善目前的治疗方案 重点是针对神经系统的药物。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，他们长期以来成功地 作为一个团队，以单一目标有效地工作，以开发促进HIV-1控制的产品。

项目成果

The COVID-19 Pandemic: Reflections of Science, Person, and Challenge in Academic Research Settings.

• DOI: 10.1007/s11481-021-10035-2
• 发表时间: 2021-12
• 期刊: Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
• 作者: Bidlack JM;Chang SL;Fitting S;Gendelman HE;Gorantla S;Kumar S;Marcondes MCG;Meigs DD;Melendez LM;Sariyer IK;Yelamanchili S
• 通讯作者: Yelamanchili S