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

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 介导CD 4 + T细胞死亡，并在ART下的免疫恢复不良中发挥作用。 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。 这条线的调查具有巨大的治疗潜力，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。

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.