Immune Dysfunction in HIV+ Opioid Users

HIV 阿片类药物使用者的免疫功能障碍

• 批准号: 10001242
• 负责人: Savita Pahwa
• 金额: $ 79.47万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10001242
• 关键词: AIDS/HIV problem; Address; Adult; Affinity; Analgesics; Antibodies; Antibody Formation; Antibody Response; Antigens; Area; B-Lymphocytes; Blood specimen; Brain; CD4 Positive T Lymphocytes; Cell Count; Cell Maturation; Cells; Cessation of life; Characteristics; Chronic; Cities; Clinic; Coupled; Dangerousness; Data; Data Set; Defect; Dependence; Development; Epidemic; Evaluation; Exhibits; Failure; Feasibility Studies; Flow Cytometry; Frequencies; Functional disorder; Future; Generations; Genetic Transcription; Genomic approach; HIV; HIV Infections; HIV Seronegativity; Helper-Inducer T-Lymphocyte; Human; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunocompetence; Immunoglobulin Somatic Hypermutation; Immunologics; Impairment; In Vitro; Incidence; Inflammation; Inflammatory; Influenza; Influenza A Virus, H1N1 Subtype; Influenza vaccination; Interleukin-2; Intervention; Lead; Lymphoid; Memory; Memory B-Lymphocyte; Morphine; Nucleic Acids; Opiate Addiction; Opioid; Opioid Receptor; Participant; Patients; Peripheral; Personal Satisfaction; Phenotype; Plasma; Plasmablast; Play; Population; Property; Receptor Signaling; Recovery; Research; Resolution; Seasons; Serological; Signal Transduction; Structure of germinal center of lymph node; Subgroup; Surface; T-Lymphocyte Subsets; Technology; Testing; Universities; Vaccinated; Vaccination; Vaccine Antigen; Vaccines; Viral; addiction; base; delta opioid receptor; drug abuser; flu; functional disability; genomic platform; immune activation; immune function; indexing; inflammatory marker; influenza virus vaccine; insight; interest; neglect; novel; opioid epidemic; opioid injection; opioid use; opioid user; peripheral blood; prescription opioid; prevent; programs; receptor; recruit; responders and non-responders; response; seasonal influenza; single cell technology; therapeutic vaccine; tool; transcriptomics; trivalent influenza vaccine; vaccine response; virology

HIV infection impairs immunity and immune perturbations persist even after durable virologic control. This population has a high incidence of using prescription opioids or injection opioids that lead to dependence. Opioids are known to be immunosuppressive, and the combination of HIV and opioids can potentially prove to be disastrous for the immune system, yet this area has been grossly understudied. Our recent project on immunity in HIV (AI108472) utilized influenza vaccination as a probe for assessing immunity in HIV+. We observed that HIV+ had lower vaccine responses than uninfected, and a subgroup of HIV+ drug abusers had worse antibody response than non-abusers. We could classify participants as vaccine responders (VR) and vaccine non-responders (VNR). In studying mechanisms of immune defects in VNR, we identified quantitative and qualitative defects in peripheral T follicular helper cells (pTfh), which are a subset of CD4 T cells that are essential for vaccine-induced antibody responses. The pTfh displayed a skewed polarization away from a favorable IL-21 secreting phenotype towards a detrimental IL-2 secreting Th1 phenotype, coupled with abundance of inflammatory markers, resulting in failure of pTfh to provide B cells with the helper signals required for secreting antibodies. Our central hypothesis is that chronic opioid use blunts the immune response to impair the generation of antibodies and exacerbates the immune dysfunction of HIV even in virally controlled patients. We will recruit opioid users and non- users in HIV negative and virally suppressed HIV+ populations to address key questions on the effect of opioids on the antibody response following seasonal influenza vaccination. The project has 3 aims: 1. To evaluate basal state of inflammation and immune/activation in relation to pTfh phenotype and the magnitude and quality of flu vaccine response. 2. To characterize pTfh by phenotypic, functional and transcriptomic analyses and 3. To test interventions for potential reversal of opioid induced immune deficiency in VNR. We will use a combination of single cell technologies to gain high resolution datasets including multi-parameter flow cytometry and the 10x single cell genomics platform combined with indexed surface marker expression using novel nucleic acid-tagged antibodies. In order to gain a comprehensive understanding on the topic of opioid effect on immune function in presence of HIV infection, we will evaluate immune cells ex vivo from the populations of interest using unbiased genomics approaches to obtain a snapshot of immune perturbation compared to healthy controls. In vitro studies with purified cell subsets and addition of morphine during antigen exposure will allow for mechanistic evaluation of opioid impact on the immune system. These studies are feasible, given our expertise in the technologies described and access to the required population through our ID Clinics and specialized programs dealing with opioid addicted populations. We expect to provide novel insight into immune perturbations that will help in strategizing vaccine approaches, including those for opioid vaccines.

即使在持久的病毒控制后，HIV感染也会损害免疫力和免疫扰动。这 人群使用处方阿片类药物或注射阿片类药物的发生率很高，导致依赖性。 已知阿片类药物是免疫抑制的，艾滋病毒和阿片类药物的结合可能会证明 对于免疫系统来说是灾难性的，但该区域已被严格研究。我们最近的项目 HIV中的免疫力（AI108472）利用流感疫苗接种作为评估HIV+免疫力的探针。我们 观察到HIV+的疫苗反应低于未感染的疫苗，而HIV+药物的亚组 抗体反应较差。我们可以将参与者归类为疫苗反应者（VR） 和疫苗非反应器（VNR）。在研究VNR免疫缺陷的机制时，我们确定了 周围T卵泡辅助细胞（PTFH）的定量和定性缺陷，这是CD4 T的子集 对于疫苗诱导的抗体反应必不可少的细胞。 PTFH显示了偏振 远离有利的IL-21分泌表型转向有害的IL-2分泌Th1表型， 再加上丰富的炎症标记，导致PTFH未能为B细胞提供 分泌抗体所需的助手信号。我们的中心假设是慢性阿片类药物使用钝 免疫反应损害抗体的产生并加剧HIV的免疫功能障碍 即使在病毒控制的患者中。我们将招募艾滋病毒和病毒hiv中的阿片类药物用户和非用户 抑制HIV+种群，以解决有关阿片类药物对抗体反应影响的关键问题 季节性流感疫苗接种。该项目有3个目标：1。评估炎症的基础状态 与PTFH表型以及流感疫苗反应的大小和质量有关的免疫/激活。 2。通过表型，功能和转录组分析和3。测试干预措施来表征PTFH 对于阿片类药物诱导的VNR免疫缺陷的潜在逆转。我们将使用单个单元组的组合 获得高分辨率数据集的技术，包括多参数流式细胞术和10倍单一 细胞基因组学平台与索引表面标记的表达相结合，使用了新型核酸标记 抗体。为了对阿片类药物对免疫功能的影响有全面的了解 在存在HIV感染的情况下，我们将使用感兴趣的种群评估免疫细胞 与健康对照组相比，公正的基因组学方法可以获得免疫扰动的快照。 通过纯化的细胞亚群研究和在抗原暴露期间添加吗啡的体外研究将允许 阿片类药物对免疫系统的影响的机理评估。考虑到我们的这些研究是可行的 通过我们的ID诊所和对所需人群进行描述和访问的技术专业知识 专门针对阿片类药物上瘾人群的专业计划。我们希望提供新颖的见解 免疫扰动将有助于制定战略疫苗方法，包括阿片类疫苗的方法。