Multi-Species Mechanisms of Drug Bio-distribution in HIV Tissue Reservoirs

HIV组织储库中药物生物分布的多物种机制

• 批准号: 8706563
• 负责人: Angela D Kashuba
• 金额: $ 80.85万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8706563
• 关键词: Affinity; Anatomic Sites; Anatomy; Animal Model; Anti-Retroviral Agents; Area; Biodistribution; Biological Assay; Cells; Clinical Research; Data; Drug Exposure; Drug Targeting; Drug or chemical Tissue Distribution; Evolution; Future; Gastrointestinal tract structure; Genitourinary system; Goals; HIV; HIV Infections; HIV therapy; HIV-1; Highly Active Antiretroviral Therapy; Human; Infection; International; Intracellular Space; Lymphoid Tissue; Measures; Methods; Modeling; Morbidity - disease rate; Mus; Neuraxis; Nucleotides; Patients; Pattern; Penetration; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Physiological; Plasma; Play; Process; Production; Protein Binding; Proteins; RNA; Regimen; Research; Residual state; Reverse Transcriptase Inhibitors; Role; Scientist; Site; Source; Spatial Distribution; Technology; Tissues; Viral; Viremia; Virus Replication; Work; antiretroviral therapy; design; drug development; drug distribution; drug efficacy; drug mechanism; extracellular; insight; mortality; nonhuman primate; novel; novel strategies; nucleoside analog; public health relevance; species difference; treatment effect

DESCRIPTION (provided by applicant): Highly sensitive HIV RNA assays have demonstrated that viral replication persists in patients with clinically suppressed viral replication in their plasma. A number of anatomic sites have been proposed as the source of persistent viral production including the gastrointestinal tract, the central nervous system, lymphoid tissue, and the genitourinary system. Humanized mice and nonhuman primates are models for HIV infection, persistence, and eradication, yet no data currently exist to evaluate inter-species similarities or differences in drug distribution to these sites. This causes difficulty in applying research findings from one species to another, including extrapolating to humans. In addition, no information on intracellular drug distribution within the aforementioned anatomic tissues has been generated. Finally, there is limited information on factors responsible for drug distribution and activity at these sites, including protein binding, drug transporter activity, and (in the caseof nucleoside analogue reverse transcriptase inhibitors) intracellular endogenous nucleotide concentrations. The hypothesis for this project is: residual active viral reservoirs are a consequence of reduced antiretroviral penetration into target tissue cell subtypes, and a thorough understanding of tissue drug distribution between species must be conducted before rational intensification regimens can be designed. Three specific aims are proposed: 1) In tissues implicated as active reservoirs, characterize distribution of 6 commonly used antiretrovirals from 5 drug classes in models of infected and uninfected humanized mice, nonhuman primates, and HIV+ subjects 2) Investigate important physiologic factors that may be responsible for antiretroviral activity and distribution, including protein binding, intracellular endogenous nucleotide concentrations, and drug transporter expression. 3) Develop a novel IR-MALDESI-MSI approach to visualize the dispersion of drugs across tissue reservoirs for all three species, and assess the role of this technology for future tissue studies in HIV infection and therapy. The goal of this work is to identify what species differences and pharmacologic barriers exist in extracellular and intracellular antiretroviral biodistribution and efficacy in eliminating active HIV reservoirs. Data generated from this proposal will enable the rational selection of antiretrovirals well suited to target active reservoirs, determine the pharmacologic advantages and limitations of animal models of HIV infection, and develop a novel strategy to measure cross-sectional drug dispersion in tissues.

描述(由申请人提供)：高灵敏度的HIV RNA分析已经证明，在临床上病毒复制受到抑制的患者的血浆中，病毒复制仍然存在。一些解剖部位被认为是持续病毒产生的来源，包括胃肠道、中枢神经系统、淋巴组织和泌尿生殖系统。人源化的小鼠和非人灵长类动物是HIV感染、持久性和根除的模型，但目前还没有数据来评估这些地点药物分配的物种间相似性或差异。这造成了应用上的困难。 从一个物种到另一个物种的研究结果，包括对人类的推断。此外，还没有关于上述解剖组织内药物分布的信息。最后，关于导致药物在这些部位的分布和活性的因素的信息有限，包括蛋白质结合、药物转运体活性以及(在核苷类似物逆转录酶抑制剂的情况下)细胞内内源核苷酸浓度。该项目的假设是：残留的活性病毒库是抗逆转录病毒对靶组织细胞亚型渗透减少的结果，在设计合理的强化方案之前，必须彻底了解组织药物在物种之间的分布。提出了三个具体的目标：1)在被认为是活性储存库的组织中，表征来自5个药物类别的6种常用抗逆转录病毒药物在感染和未感染的人源化小鼠、非人灵长类动物和HIV+受试者模型中的分布；2)研究可能影响抗逆转录病毒活性和分布的重要生理因素，包括蛋白结合、细胞内核苷酸浓度和药物转运体的表达。3)开发一种新的IR-Maldesi-MSI方法，以可视化药物在所有三个物种的组织储存库中的分散，并评估该技术在未来艾滋病毒感染和治疗的组织研究中的作用。这项工作的目标是确定细胞外和细胞内抗逆转录病毒生物分布中存在哪些物种差异和药理障碍，以及在消除活跃的艾滋病毒宿主方面的有效性。这项提议产生的数据将使人们能够合理地选择非常适合于目标活性储存库的抗逆转录病毒药物，确定艾滋病毒感染动物模型的药理学优势和局限性，并开发一种新的战略来测量药物在组织中的横截面扩散。