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: 10595555
• 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/10595555
• 关键词: Accounting; Affinity; Antibodies; Antibody-Producing Cells; Antigens; Area; Autoantibodies; Avidity; B-Cell Antigen Receptor; 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 Data; 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; Population; Production; Property; Public Health; Publishing; Recovery; Reporting; Role; Signal Pathway; Signal Transduction; Sorting; 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CD4+ T细胞计数预测疾病进展。即使在长期抑制下 抗逆转录病毒疗法（ART），多达25％的病毒学抑制艾滋病毒（PLWH）未能恢复 CD4+ T细胞计数达到与健康对照中类似的水平，发病率和死亡率的增加具有 在这些免疫无反应器中得到了证明。我们是第一个报告抗CD4 IgGS的组 介导CD4+ T细胞死亡，并在ART下的免疫恢复不良中发挥作用。而发病机理可能 多因素，例如胸腺和淋巴纤维化，全身免疫激活和炎症，我们 提出的病理抗CD4 IgG介导的CD4+ T细胞耗竭提供了靶向的独特机制 CD4+ T细胞特别。在当前的研究中，我们将研究病理抗 - 的分子机制 来自免疫无反应器的CD4 IgG和抗CD4自动反应性B细胞，并识别治疗靶标 为了防止抗CD4 IgG介导的发病机理以及传统艺术以增加免疫恢复和 减少艾滋病毒+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CD4 IgGs在CD4+ T细胞激活和功能和HIV上的病理活性 通过HIV+免疫非反应器中的CD4受体信号通路的潜伏期。 目标2。确定抗CD4自身抗体的B细胞受体特征和基因表达景观 由HIV+免疫非反应者产生B细胞。 目标3。确定病理抗CD4的生化特性和共享抗原结合表位 HIV+免疫无反应者中的单克隆IgG。 这一调查线对退伍军人和非退伍军人HIV阳性具有巨大的治疗潜力 表现不佳的CD4+ T细胞回收率较差的个体，人口特别高的发病风险和 死亡率，因此是公共健康重要性的领域。