HIV Theranostic

HIV治疗诊断

• 批准号: 10021713
• 负责人: Prasanta Kumar Dash
• 金额: $ 68.6万
• 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/10021713
• 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; 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; combat; 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

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