Investigate the mechanism of autoreactive B cell-mediated immunological failure despite virologic suppression in HIV-infected individuals on antiretroviral therapy

研究尽管接受抗逆转录病毒治疗的 HIV 感染者出现病毒学抑制，但自身反应性 B 细胞介导的免疫失败的机制

• 批准号: 10368232
• 负责人: Wei Jiang
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10368232
• 关键词: Accounting; Affinity; Antibodies; Antibody-Producing Cells; Antigens; Area; Autoantibodies; Avidity; B-Cell Antigen Receptor; B-Lymphocyte Epitopes; B-Lymphocytes; B-cell receptor repertoire sequencing; Binding; Biochemical; Blood specimen; CD4 Antigens; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Count; Cell Death; Cell Line; Cell physiology; Cells; Cessation of life; Characteristics; Clinical; Common Epitope; Cryopreservation; Data Set; Development; Disease Progression; Epitope Mapping; Epitopes; Failure; Fibrosis; Flow Cytometry; Gene Expression; Genes; Genomics; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV Seropositivity; Hospitals; Immune; Immunoglobulin G; Immunologics; In Vitro; Individual; Inflammation; Influenza; Intervention; Investigation; Light; Lymphatic; Mediating; Messenger RNA; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Pathogenesis; Pathologic; Peripheral Blood Mononuclear Cell; Persons; Plasma; Play; Population; Production; Property; Public Health; Publishing; Recovery; Reporting; Role; Signal Pathway; Signal Transduction; Specificity; Surface; T cell reconstitution; T-Cell Activation; T-Cell Depletion; TLR2 gene; TLR4 gene; Testing; Therapeutic; Thymus Gland; Veterans; Work; antibody-dependent cell cytotoxicity; antigen binding; antiretroviral therapy; autoreactive B cell; high risk; immune activation; inhibitor; latent HIV reservoir; latent infection; mortality; prevent; recruit; targeted treatment; therapeutic target; transcriptome sequencing

In HIV infection, circulating CD4+ T cell counts predict disease progression. Even under long-term suppressive antiretroviral therapy (ART), up to 25% of virologically suppressed people living with HIV (PLWH) fail to restore CD4+ T cell counts to the levels similar to those in healthy controls, and increased morbidity and mortality have been demonstrated in these immune non-responders. We were the first group to report that anti-CD4 IgGs mediate CD4+ T cell death and play a role in poor immune recovery under ART. While the pathogenesis is likely multifactorial, such as thymic and lymphatic fibrosis, systemic immune activation, and inflammation, our proposed pathologic anti-CD4 IgG-mediated CD4+ T cell depletion provides a unique mechanism for targeting CD4+ T cells specifically. In the current study, we will investigate the molecular mechanisms of pathologic anti- CD4 IgGs and anti-CD4 autoreactive B cells from immune non-responders and identify the therapeutic targets to prevent anti-CD4 IgG-mediated pathogenesis together with traditional ART to increase immune recovery and reduce complications, morbidity and mortality in HIV+ Veterans and non-Veterans. AIM 1. Determine the pathologic activities of anti-CD4 IgGs on CD4+ T cell activation and function and HIV latency through the CD4 receptor signaling pathway in HIV+ immune non-responders. AIM 2. Determine the B cell receptor characteristics and gene expression landscape of anti-CD4 autoantibody- producing B cells from HIV+ immune non-responders. AIM 3. Determine the biochemical properties and shared antigen binding epitopes of pathologic anti-CD4 monoclonal IgGs in HIV+ immune non-responders. This line of investigation possesses great therapeutic potential for Veteran and non-Veteran HIV-positive individuals presenting with poor CD4+ T cell recovery, a population with particularly high risk for morbidity and mortality and thus an area of public health importance.

在HIV感染中，循环CD 4 + T细胞计数可预测疾病进展。即使在长期的压抑下， 抗逆转录病毒疗法（ART），高达25%的病毒学抑制的艾滋病毒感染者（PLWH）未能恢复 CD 4 + T细胞计数水平与健康对照组相似，发病率和死亡率增加， 在这些免疫无应答者中得到证实。我们是第一个报告抗CD 4 IgG的小组 介导CD 4 + T细胞死亡，并在ART下免疫恢复不良中发挥作用。虽然发病机制可能是 多因素，如胸腺和淋巴纤维化，全身免疫激活和炎症，我们的 提出的病理性抗CD 4 IgG介导的CD 4 + T细胞耗竭提供了一种独特的靶向机制 CD 4 + T细胞。在本研究中，我们将探讨病理性抗- 免疫无应答者的CD 4 IgG和抗CD 4自身反应性B细胞，并确定治疗靶点 与传统ART一起预防抗CD 4 IgG介导的发病机制，以增加免疫恢复， 减少艾滋病毒阳性退伍军人和非退伍军人的并发症、发病率和死亡率。 AIM 1.确定抗CD 4 IgG对CD 4 + T细胞活化和功能以及HIV的病理活性 HIV+免疫无应答者中通过CD 4受体信号传导途径的潜伏期。 AIM 2.确定抗CD 4自身抗体的B细胞受体特征和基因表达谱- 从HIV+免疫无应答者产生B细胞。 AIM 3.确定病理性抗CD 4抗体的生化特性和共有抗原结合表位 HIV+免疫无应答者中的单克隆IgG。 这条线的调查具有很大的治疗潜力的退伍军人和非退伍军人艾滋病毒阳性 CD 4 + T细胞恢复差的个体，发病风险特别高的人群， 死亡率，因此是一个具有公共卫生重要性的领域。