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

项目总结/摘要 在HIV感染中，循环CD 4 + T细胞计数可预测疾病进展。在感染者中，高达25% 的抗逆转录病毒疗法（ART）治疗的艾滋病毒感染者（PWH）（约111，000人）未能恢复其外周血 CD 4 + T细胞计数降至健康对照水平，发病率和死亡率增加， 在这些免疫重建失败的患者中证实。物质使用障碍在 艾滋病毒感染者和滥用药物的人与病毒感染者中CD 4 + T细胞恢复不良有关， 在这项研究中，我们将研究可卡因如何影响自身反应性B细胞功能。我们 第一组报道抗CD 4自身抗体通过抗体介导的CD 4 + T细胞死亡， 细胞毒性（ADCC），并导致抑制性ART下CD 4 + T细胞恢复不良。 表明可卡因或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CD 4自身抗体的产生， PWH。我们的目标是改善CD 4 + T细胞的恢复，降低HIV+可卡因使用者的死亡率和发病率。 抑制性ART。 目的1：确定左旋咪唑污染的可卡因使用与HIV+患者血浆抗CD 4 IgG水平的关系。 可卡因使用者服用抑制性抗逆转录病毒药物 目的2：在HIV+左旋咪唑污染的可卡因中表征产生抗CD 4 IgG的单个B细胞基因“签名 使用抑制性抗逆转录病毒药物。

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.