On the pathogenic role of anti-CD4 antibody in poor CD4+ T cell recovery after antiretroviral therapy in HIV disease

抗 CD4 抗体在 HIV 疾病抗逆转录病毒治疗后 CD4 T 细胞恢复不良中的致病作用

• 批准号: 9921289
• 负责人: Wei Jiang
• 金额: $ 20.79万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-19 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9921289
• 关键词: Acute; Address; Anti-Retroviral Agents; Antibodies; Antigens; Apoptosis; Apoptotic; Autoantibodies; B-Lymphocytes; Binding; Blood; Blood specimen; CD4 Positive T Lymphocytes; Cell Count; Cell Death; Cell-Mediated Cytolysis; Cells; Chronic; Development; Disease; Fibrosis; Genes; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV antiretroviral; HIV therapy; HIV vaccine; Human; Human Cell Line; Immune; Immune Plasma; Immunoglobulin G; Immunoglobulin Somatic Hypermutation; Immunologics; Immunotherapy; In Vitro; Individual; Kinetics; Location; Mediating; Monoclonal Antibodies; Morbidity - disease rate; NK Cell Activation; Natural Killer Cells; Pathogenesis; Pathogenicity; Patients; Plasma; Proteins; Receptors, Antigen, B-Cell; Recovery; Role; Sampling; Specificity; Surface; T cell reconstitution; T-Cell Activation; T-Lymphocyte Subsets; Therapeutic; Thymus Gland; Time; Vaccine Design; Viral; Virus Diseases; Virus Replication; acute infection; antibody-dependent cell cytotoxicity; antiretroviral therapy; autoreactive B cell; chronic infection; cytotoxicity; design; human study; immune function; improved; inhibitor/antagonist; lymph nodes; mortality; restoration; therapeutic development; virology

Human immunodeficiency virus (HIV) disease has been significantly controlled following the introduction of antiretroviral therapy (ART) [1]. This treatment dramatically improves immune function, suppresses HIV viral replication, and decreases morbidity and mortality [1, 2]. However, up to 25% of virologically suppressed individuals (~111,000 people in USA) fail to restore their CD4+ T cells to counts > 350 cells/µL, even after long- term ART treatment and viral suppression [3], and increased morbidity and mortality have been observed in these patients [4-7]. Thymic fibrosis has been suggested a mechanism, and low nadir CD4+ T cell counts and T cell activation have been shown to associate with incomplete immune restoration after ART treatment [8-11], but mechanisms for immune non-response remain largely unknown. To better understand mechanisms of incomplete immune restoration, we performed a preliminary human study in 12 healthy controls, 17 immunologic responders (IRs) (aviremic and ART treated > 3 years, and CD4+ T cell counts > 500 cells/µL) and 11 immunologic non-responders (INRs) (aviremic and ART treated > 3 years, and CD4+ T cell counts < 350 cells/µL) [8]. Elevated plasma levels of anti-CD4 IgGs were found in patients compared to controls and correlated with blunted CD4+ T cell recovery. Furthermore, purified anti-CD4 IgGs from plasma of aviremic long-term ART-treated subjects with CD4+ T cell counts below 350 cells/µl, defined as “immunologic non- responders”, induced antibody-dependent NK cell-mediated cytotoxicity against CD4+ T cells. We hypothesize that heightened level of anti-CD4 Ab contributes to the pathogenesis of CD4+ T cell losses in HIV infection. If our hypothesis is correct, a therapeutic strategy that targeting autoreactive B cells or anti-CD4 Abs could potentially optimize ART treatment to improve CD4+ T cell recovery and reduce mortality and morbidity in treated HIV-infected patients. This study will also provide important information in HIV vaccine design.

人类免疫缺陷病毒(HIV)疾病在引入 抗逆转录病毒疗法(ART)[1]。这种疗法显著提高了免疫功能，抑制了HIV病毒 复制，并降低发病率和死亡率[1，2]。然而，高达25%的病毒学抑制 个人(在美国约111,000人)无法将他们的CD_4+T细胞恢复到计数为350个/µL，即使在长时间的 定期抗逆转录病毒治疗和病毒抑制[3]，以及增加的发病率和死亡率已经观察到在 这些患者[4-7]。胸腺纤维化已被认为是一种机制，低水平的CD4+T细胞计数和 T细胞的激活已被证明与ART治疗后的不完全免疫恢复有关[8-11]， 但免疫无反应的机制在很大程度上仍不清楚。为了更好地了解 不完全的免疫恢复，我们在12名健康对照中进行了初步的人体研究，17名 免疫应答者(无药和抗逆转录病毒治疗3年，CD 4+T细胞计数500个/µL) 11例免疫无反应(INRS)(无菌治疗和ART治疗3年，CD4+T细胞计数&lt； 350个细胞/微米L)[8]。与对照组相比，患者血浆中抗CD4Igs水平升高。 与钝化的CD4+T细胞恢复有关。此外，从无毒症小鼠血浆中提纯了抗CD4Igs 长期接受抗逆转录病毒治疗的CD_4+T细胞计数低于350个/微米的受试者L，定义为“免疫性非 应答者“，诱导抗体依赖的NK细胞介导的对CD4+T细胞的细胞毒作用。我们假设 高水平的抗CD4Ab参与了HIV感染中CD4+T细胞丢失的发病机制。如果 我们的假设是正确的，靶向自身反应性B细胞或抗CD4抗体的治疗策略可能 有可能优化ART治疗，以改善CD4+T细胞恢复并降低死亡率和发病率 治疗艾滋病毒感染者。这项研究还将为艾滋病毒疫苗的设计提供重要信息。