Defining the impact of drug use on immune function and fitness against HIV-1

确定吸毒对免疫功能和抗 HIV-1 适应性的影响

• 批准号: 10238552
• 负责人: Alex K Shalek
• 金额: $ 117.6万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10238552
• 关键词: Biological; Biopsy; Boston; Cells; Chemicals; Clinical; Communities; Development; Disease; Drug usage; Environmental Risk Factor; Equipment; Exposure to; Gastrointestinal tract structure; General Population; Genomics; Goals; HIV-1; Health; Human; Immune response; Immune system; Immunity; Immunologics; Incidence; Individual; Infection; Injecting drug user; Investigation; Knowledge; Liver; Methods; Molecular; Mucous Membrane; National Institute of Drug Abuse; Opioid; Peripheral Blood Mononuclear Cell; Physiology; Positioning Attribute; Prevention; Prevention strategy; Resolution; Risk; Sampling; Technology; Test Result; Testing; Therapeutic; Tissues; Treatment Efficacy; Work; design; drug metabolism; experience; fitness; immune function; immunoregulation; improved; innovation; insight; novel; opioid use; opioid use disorder; pathogen; polysubstance use; programs; prophylactic; screening; social; tool

PAR-20-221: NIDA Avant-Garde - Abstract Alex K. Shalek ABSTRACT HIV-1 prevention and cure strategies are urgently needed for people who inject drugs (PWID) with opioid use disorder (OUD) or polysubstance used disorder (PSUD) given substantial risk for, and incidence of, HIV-1 and others infection. Most prophylactic and therapeutic strategies under development for HIV-1 and other infections rely on modulating host immunity. Nevertheless, we do not have a working knowledge of how opioids—which, themselves, are immunomodulatory—and the lived experiences of those with OUD or PSUD (inclusive of exposure to contaminated equipment, community infections, and physical and social environmental factors) alter immune function in the absence or presence of HIV-1 infection and, thus, the efficacy of interventions against HIV-1 and other pathogens. We hypothesize that opioids and OUD/PSUD modulate baseline immune responses in the host (“function”), as well as immunity against other pathogens (“fitness”), impacting prevention and cure strategies. Here, we propose a pioneering program to define, at unprecedented resolution, the cellular and molecular impact of OUD and PSUD on immune function and response to pathogens, such as HIV-1. We will also develop and utilize an innovative “compressed’ screening platform to functionally test, in high-throughput, informed chemical and biological perturbations for prevention and cure strategies. More specifically, we will deploy—and, where necessary, develop—cutting-edge single-cell and bulk genomic profiling methods to generate functional hypotheses on how OUD and PSUD alter critical physiology associated with drug metabolism (liver), innate mucosal defense (gastrointestinal tract (GI)), and adaptive immune function in tissues of relevance to HIV-1 (liver, GI, and peripheral blood mononuclear cells (PBMCS)). We will explicitly characterize and contrast changes in the presence and absence of HIV-1 infection. To systematically test resulting hypotheses, we will create and implement “compressed” perturbation screens to examine simultaneously the individual impact of multiple chemical and biological perturbations on limited primary samples (e.g., PBMCs, tissue biopsies). This will enable us to delineate how factors associated with several aspects of OUD and PSUD intersect with HIV-1 infection. Given my lab’s broad and yet deep interdisciplinary expertise in developing and applying innovative experimental and computational technologies to obtain mechanistic insights into the cellular and molecular drivers of human health and disease, and our team of committed clinical collaborators in Boston and beyond, we are uniquely positioned to successfully execute this pioneering, transformative investigation of the impact of OUD and PSUD on immune function. Overall, our work will define the immunological landscape of OUD and PSUD, and inform strategies to improve baseline immunity and the efficacy of preventions and cures against HIV-1 and other pathogens for those with OUD and OSUD, and the general population.

PAR-20-221：NIDA 前卫 - 摘要 Alex K. Shalek 抽象的 使用阿片类药物注射吸毒者 (PWID) 迫切需要 HIV-1 预防和治疗策略 HIV-1 和多物质使用障碍 (OUD) 或多物质使用障碍 (PSUD) 具有重大风险和发病率 其他人感染。大多数针对 HIV-1 和其他感染的预防和治疗策略正在开发中 依赖调节宿主免疫力。然而，我们对阿片类药物如何运作缺乏了解。 本身具有免疫调节作用，并且 OUD 或 PSUD 患者的生活经历（包括 接触受污染的设备、社区感染以及物理和社会环境因素）会改变 在不存在或存在 HIV-1 感染的情况下的免疫功能，以及因此干预措施的有效性 HIV-1 和其他病原体。我们假设阿片类药物和 OUD/PSUD 调节基线免疫反应 在宿主体内（“功能”），以及对其他病原体的免疫力（“适应性”），影响预防和治疗 策略。在这里，我们提出了一项开创性的计划，以前所未有的分辨率定义细胞和 OUD 和 PSUD 对免疫功能和对病原体（如 HIV-1）反应的分子影响。我们将 还开发并利用创新的“压缩”筛选平台进行高通量功能测试， 为预防和治疗策略提供化学和生物扰动的信息。更具体地说，我们将 部署并在必要时开发尖端的单细胞和批量基因组分析方法 生成关于 OUD 和 PSUD 如何改变与药物代谢相关的关键生理学的功能假设 （肝脏）、先天粘膜防御（胃肠道 (GI)）以及相关组织中的适应性免疫功能 HIV-1（肝脏、胃肠道和外周血单核细胞 (PBMCS)）。我们将明确地描述和对比 HIV-1 感染存在与否的变化。为了系统地检验由此产生的假设，我们将 创建并实施“压缩”扰动屏幕，以同时检查个体影响 对有限的原始样本（例如 PBMC、组织活检）进行多种化学和生物扰动。这 将使我们能够描述与 OUD 和 PSUD 几个方面相关的因素如何与 HIV-1 交叉 感染。鉴于我的实验室在开发和应用创新方面拥有广泛而深入的跨学科专业知识 实验和计算技术以获得细胞和分子机制的见解 人类健康和疾病的驱动因素，以及我们在波士顿及其他地区的忠诚临床合作者团队， 我们拥有独特的优势，能够成功地开展这项开创性、变革性的影响调查 OUD 和 PSUD 对免疫功能的影响。总的来说，我们的工作将定义 OUD 和 PSUD，并提供提高基线免疫力和预防和治疗功效的策略 针对 OUD 和 OSUD 患者以及普通人群的 HIV-1 和其他病原体。