Investigate B cell perturbations and immune reconstitution failure in response to antiretroviral therapy in HIV-infected cocaine users

调查感染 HIV 的可卡因使用者抗逆转录病毒治疗导致的 B 细胞扰动和免疫重建失败

• 批准号: 10677040
• 负责人: Wei Jiang
• 金额: $ 15.1万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10677040
• 关键词: Acquired Immunodeficiency Syndrome; Aminorex; Antibodies; Area; Autoantibodies; Autoimmune Diseases; Award; B-Lymphocytes; Binding; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cardiovascular Diseases; Cell Count; Cell Death; Cell physiology; Cells; Chronic; Clinic; Clinical; Clinical Data; Cocaine; Cocaine Users; Cryopreservation; Data Set; Disease; Disease Progression; Drug usage; Epitopes; Failure; Fibrosis; Flow Cytometry; Funding; Genes; Goals; HIV; HIV Infections; HIV therapy; Harm Reduction; Hospitalization; Immunoglobulin G; Immunologics; Infection; Inflammation; Investigation; Levamisole; Lymphatic; Mediating; Medical; Molecular; Monoclonal Antibodies; Morbidity - disease rate; National Institute of Drug Abuse; Pathogenesis; Pathogenicity; Patient Care; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Plasma; Population; Production; Prothrombin; Public Health; Publishing; Recovery; Reporting; Research; Resources; Sampling; Science; South Carolina; Substance Use Disorder; T-Cell Depletion; Testing; Therapeutic; Thymus Gland; Time; Universities; Urine; Viral; Work; advanced disease; antibody-dependent cell cytotoxicity; antiretroviral therapy; autoreactive B cell; cocaine use; cost; drug of abuse; genetic signature; high risk; immune activation; immune reconstitution; improved; inhibitor; mortality; prevent; recruit; response; test strip

PROJECT SUMMARY/ABSTRACT In HIV infection, circulating CD4+ T cell counts predict disease progression. Among infected subjects, up to 25% of antiretroviral therapy (ART)-treated people with HIV (PWH) (~111,000 people) fail to restore their peripheral CD4+ T cell counts to the levels of healthy controls, and increased morbidity and mortality have been demonstrated in these patients with immune reconstitution failure. Substance use disorders are common among people who are HIV infected, and drug of abuse is associated with poor CD4+ T cell recovery in patients on viral- suppressive ART. In this study, we will investigate how cocaine impacts on autoreactive B cell functions. We are the first group to report that anti-CD4 autoantibodies mediate CD4+ T cell death via antibody-mediated cytotoxicity (ADCC) and contribute to poor CD4+ T cell recovery under suppressive ART. Previous studies indicate that cocaine or levamisole-tainted cocaine (69% of cocaine is contaminated with levamisole) is able to induce autoantibodies and clinical presentations of autoimmune diseases. Thus, we hypothesize that cocaine or levamisole-tainted cocaine activates autoreactive B cells and promotes anti-CD4 autoantibody production in PWH. Our goal is to improve CD4+ T cell recovery and reduce mortality and morbidity in HIV+ cocaine users on suppressive ART. AIM 1: Determine the association of levamisole-tainted cocaine use and plasma anti-CD4 IgG levels in HIV+ cocaine users on suppressive ART. AIM 2: Characterize anti-CD4 IgG-producing single B cell gene “signature” in HIV+ levamisole-tainted cocaine users on suppressive ART.

项目摘要/摘要 在HIV感染中，循环中的CD4+T细胞计数可以预测疾病的进展。在受感染的受试者中，高达25% 接受抗逆转录病毒疗法(ART)治疗的HIV(PWH)患者(约111,000人)未能恢复其外周血细胞 CD4+T细胞计数达到健康对照组的水平，发病率和死亡率一直在上升 在这些免疫重建失败的患者中表现出。物质使用障碍在以下人群中很常见 HIV感染者，滥用药物与接受病毒治疗的患者CD4+T细胞恢复不良有关- 压抑艺术。在这项研究中，我们将研究可卡因对自身反应性B细胞功能的影响。我们是 第一个报告抗CD4自身抗体通过抗体介导的CD4+T细胞死亡的小组 细胞毒性(ADCC)，并在抑制ART的情况下导致CD4+T细胞恢复不良。以前的研究 表明可卡因或被左旋咪唑污染的可卡因(69%的可卡因被左旋咪唑污染)能够 诱导自身抗体和自身免疫性疾病的临床表现。因此，我们假设可卡因或 左旋咪唑污染的可卡因激活自身反应性B细胞并促进抗CD4自身抗体的产生 威尔斯亲王医院。我们的目标是改善CD4+T细胞的恢复，降低HIV+可卡因使用者的死亡率和发病率 压抑艺术。 目的1：确定受左旋咪唑污染的可卡因使用与HIV+患者血浆抗CD4Ig水平之间的关系 可卡因吸毒者对压抑艺术的看法。 目的2：表征HIV+左旋咪唑污染的可卡因中产生抗CD4Ig G的单个B细胞基因的“特征” 压抑艺术的使用者。