Immune Dysfunction in HIV+ Opioid Users

HIV 阿片类药物使用者的免疫功能障碍

基本信息

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
项目类别：
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

项目摘要

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.

HIV 感染会损害免疫力，即使在持久的病毒学控制之后，免疫扰动仍然持续存在。这人群使用处方阿片类药物或注射阿片类药物导致依赖的发生率很高。众所周知，阿片类药物具有免疫抑制作用，艾滋病毒和阿片类药物的组合可能会证明对免疫系统来说是灾难性的，但这一领域的研究却严重不足。我们最近的项目 HIV 免疫 (AI108472) 利用流感疫苗接种作为评估 HIV+ 免疫的探针。我们观察到 HIV+ 的疫苗反应低于未感染者，以及 HIV+ 吸毒者的一个亚群与非滥用者相比，抗体反应更差。我们可以将参与者归类为疫苗反应者 (VR) 和疫苗无反应者 (VNR)。在研究 VNR 免疫缺陷的机制时，我们发现外周滤泡辅助 T 细胞 (pTfh) 的定量和定性缺陷，该细胞是 CD4 T 的一个子集对于疫苗诱导的抗体反应至关重要的细胞。 pTfh 显示偏斜偏振从有利的 IL-21 分泌表型转向有害的 IL-2 分泌 Th1 表型，再加上大量的炎症标记物，导致 pTfh 无法为 B 细胞提供分泌抗体所需的辅助信号。我们的中心假设是，长期使用阿片类药物会削弱免疫反应会损害抗体的产生并加剧艾滋病毒的免疫功能障碍即使是在病毒控制的患者中。我们将招募艾滋病毒阴性和病毒感染的阿片类药物使用者和非使用者抑制艾滋病毒+人群，以解决阿片类药物对抗体反应影响的关键问题接种季节性流感疫苗后。该项目有 3 个目标： 1. 评估炎症的基础状态和与 pTfh 表型以及流感疫苗反应的程度和质量相关的免疫/激活。 2. 通过表型、功能和转录组分析来表征 pTfh，以及 3. 测试干预措施潜在逆转 VNR 中阿片类药物引起的免疫缺陷。我们将使用单细胞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 10x 单流式细胞术细胞基因组学平台与使用新型核酸标记的索引表面标记表达相结合抗体。为了全面了解阿片类药物对免疫功能的影响这一话题在存在 HIV 感染的情况下，我们将使用以下方法对来自感兴趣人群的免疫细胞进行离体评估：与健康对照相比，无偏见的基因组学方法可以获得免疫扰动的快照。使用纯化的细胞亚群进行体外研究并在抗原暴露期间添加吗啡将允许阿片类药物对免疫系统影响的机制评估。这些研究是可行的，因为我们所描述技术的专业知识以及通过我们的 ID 诊所接触到所需人群的机会针对阿片类药物成瘾人群的专门计划。我们希望提供新颖的见解免疫扰动将有助于制定疫苗方法策略，包括阿片类疫苗的疫苗方法。