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

Par-20-221：Nida Avant-Garde-Abstract Alex K.Shalek 摘要 阿片类药物注射吸毒者急需HIV-1防治策略 疾病(OUD)或多物质使用障碍(PSUD)具有相当大的艾滋病毒-1和 其他感染。针对HIV-1和其他感染正在制定的大多数预防和治疗策略 依赖于调节宿主免疫力。然而，我们并不了解阿片类药物是如何， 本身是免疫调节的--以及患有OUD或PSUD的人的生活经历(包括 暴露于受污染的设备、社区感染以及物理和社会环境因素)改变 无HIV-1感染或存在HIV-1感染时的免疫功能，以及干预措施的有效性 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 在宿主中(“功能”)以及对其他病原体的免疫力(“适合性”)，影响防治 战略。在这里，我们提出了一个开创性的计划，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的反应的分子影响，如HIV-1。我们会 还开发和利用创新的“压缩”筛选平台，在高通量、 知情的化学和生物扰动，用于预防和治疗战略。更确切地说，我们将 部署--并在必要时开发--尖端的单细胞和批量基因组图谱方法，以 生成关于OUD和PSUD如何改变与药物代谢相关的关键生理的功能假说 (肝脏)、固有粘膜防御(胃肠道(GI))和相关组织的适应性免疫功能 对HIV-1(肝脏、胃肠道和外周血单个核细胞(PBMCS))。我们将明确地描述和对比 HIV-1感染的存在和不存在的变化。为了系统地测试由此产生的假设，我们将 创建并实施“压缩的”扰动屏幕，以同时检查 对有限的初级样本(例如，外周血单核细胞、组织活检)进行多重化学和生物扰动。这 将使我们能够描绘与OUD和PSUD的几个方面相关的因素如何与HIV-1相交 感染。鉴于我的实验室在开发和应用创新技术方面拥有广泛而深厚的跨学科专业知识 实验和计算技术，以获得对细胞和分子的机械洞察 人类健康和疾病的驱动力，以及我们在波士顿和其他地区忠诚的临床合作者团队， 我们具有得天独厚的优势，能够成功开展这项开创性、变革性的调查 OUD和PSUD对免疫功能的影响。总体而言，我们的工作将定义OUD和OID的免疫学图景 PSUD，并通报战略，以提高基线免疫力和预防和治疗疟疾的有效性 HIV-1和其他病原体，适用于OUD和OSUD患者以及普通人群。

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.