Luo Zhenwu, Li Min, Mi Fuli, Meng Zhefeng, Du Guoqiang, Martin Lisa, Liu Hui, Jin Ping, Stroncek David, Heath Sonya L, Jiang Wei
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA.
Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, Shandong, China.
J Virol. 2021 May 10;95(11). doi: 10.1128/JVI.00271-21. Epub 2021 Mar 17.
Potential mechanisms of poor CD4+ T cell reconstitution after viral suppression with antiretroviral therapy (ART) in HIV disease have been extensively investigated. We recently discovered that anti-CD4 autoantibody plays a role in impaired CD4+ T cell recovery from ART in HIV-infected individuals with viral suppression, which accounts for a mechanism specific for CD4+ T cell depletion. However, the mechanism of pathologic anti-CD4 autoantibody production in treated HIV disease remains unknown. Here we report that seasonal influenza vaccination induced IgG anti-CD4 autoantibodies, predominant IgG3 subclass, in some viral-suppressed ART-treated HIV+ subjects. To explore the mechanism of anti-CD4 antibody production in this population, we performed and analyzed gene profiles in isolated B cells using a gene microarray and plasma 32 cytokines. Notably, both gene expression and multiple cytokine analyses showed pre-vaccination plasma level of IL-23 was the key cytokine linked to IgG anti-CD4 antibody production in response to immunization Exogenous rIL-23 increased autoreactive IgG binding on CD4+ T cells from HIV+ subjects Results from this study may reveal a role of IL-23 in anti-CD4 autoantibody production in treated HIV.In our published studies, we determine that pathological anti-CD4 IgGs from immunologic non-responders on virally-suppressive ART (CD4 cell counts < 350 cells/μL) mediated CD4+ T cell death via antibody-mediated cytotoxicity (ADCC), which play a role in poor CD4+ T cell recovery from ART. Up to 25% of HIV-infected individuals are non-responders and demonstrate increased morbidity and mortality. However, the mechanism of anti-CD4 autoantibody production in treated HIV remains unknown. In this study, we report that IL-23 may be the key cytokine to promote anti-CD4 autoantibody production after immunization in ART-treated HIV-infected individuals.
抗逆转录病毒疗法（ART）抑制病毒后，HIV疾病中CD4 + T细胞重建不良的潜在机制已得到广泛研究。我们最近发现，抗CD4自身抗体在病毒得到抑制的HIV感染者中，对ART治疗后CD4 + T细胞恢复受损起到作用，这是CD4 + T细胞耗竭的一种特定机制。然而，在接受治疗的HIV疾病中病理性抗CD4自身抗体产生的机制仍然未知。在此我们报告，季节性流感疫苗接种在一些病毒得到抑制且接受ART治疗的HIV +受试者中诱导产生了IgG抗CD4自身抗体，主要为IgG3亚类。为探究该人群中抗CD4抗体产生的机制，我们使用基因微阵列和血浆32种细胞因子对分离出的B细胞进行了基因谱分析。值得注意的是，基因表达和多种细胞因子分析均显示，接种疫苗前血浆中IL - 23水平是与免疫接种后IgG抗CD4抗体产生相关的关键细胞因子。外源性重组IL - 23增加了HIV +受试者CD4 + T细胞上自身反应性IgG的结合。本研究结果可能揭示了IL - 23在接受治疗的HIV中抗CD4自身抗体产生中的作用。在我们已发表的研究中，我们确定，来自病毒抑制性ART治疗的免疫无应答者（CD4细胞计数<350个细胞/μL）的病理性抗CD4 IgG通过抗体介导的细胞毒性（ADCC）介导CD4 + T细胞死亡，这在ART治疗后CD4 + T细胞恢复不良中起作用。高达25%的HIV感染者为无应答者，且发病率和死亡率增加。然而，接受治疗的HIV中抗CD4自身抗体产生的机制仍然未知。在本研究中，我们报告IL - 23可能是促进ART治疗的HIV感染者免疫接种后抗CD4自身抗体产生的关键细胞因子。
