Angin Mathieu, Fathi Anahita, King Melanie, Ledoux Mary B, Piechocka-Trocha Alicja, Altfeld Marcus, Addo Marylyn M
aRagon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA bUniversity of Münster, Münster, North Rhine-Westphalia cDepartment of Viral Immunology, Leibniz Institute for Experimental Virology, Hamburg, Germany dDivision of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA eI. Department of Medicine, University Medical Center Hamburg-Eppendorf fGerman Center for Infection Research (DZIF), Standort Hamburg-Lüebeck-Borstel, Hamburg, Germany.
AIDS. 2017 Mar 13;31(5):635-641. doi: 10.1097/QAD.0000000000001390.
Heme oxygenase-1 (HO-1) is an inducible stress response protein with potent anti-inflammatory activity and recent data suggest a potentially beneficial role in HIV pathogenesis. We investigated the impact of HO-1 and a novel subset of HO-1-specific CD8 regulatory T cells on virus-specific T-cell immunity in HIV-1-infected individuals.
HO-1 protein levels were quantified in plasma from individuals at different stages of HIV-1 disease and longitudinally following primary HIV infection. HO-1-specific CD8 T cells were investigated by flow cytometry using human leukocyte antigen (HLA) class I pentamers. Flow-sorted HO-1-specific CD8 T cells were cultured and tested for suppressive activity on HIV-1-specific cytotoxic T-cell clones clones. HO-1 gene expression was determined in sorted peripheral blood mononuclear cell (PBMC) subsets from individuals with acute HIV-1 infection.
HO-1 plasma levels were significantly increased in HIV-1 infection, with the highest levels in individuals with acute HIV-1 infection, and gradually declined over time. The frequency of CD8 T cells specific for HO-1 was elevated in study participants with primary HIV-1 infection and flow-sorted HO-1-specific CD8 T cells were capable of suppressing HIV-1-specific lysis of cytotoxic T-cell clones clones. HO-1 gene expression was upregulated in multiple immune cell subsets during acute HIV-1 infection and HO-1 overexpression modulated anti-HIV immunity in vitro.
Our data suggest that HO-1 is induced during acute HIV-1 infection, likely mediating anti-inflammatory effects and driving expansion of HO-1-specific CD8 regulatory T cells capable of suppressing HIV-1-specific immune responses in vitro. The investigation of HO-1 and the novel CD8 regulatory cell type described here provide further insight into immune regulation in HIV-1 infection and may hold potential for future immunotherapeutic intervention.
血红素加氧酶-1（HO-1）是一种具有强大抗炎活性的诱导性应激反应蛋白，近期数据表明其在HIV发病机制中可能发挥有益作用。我们研究了HO-1及HO-1特异性CD8调节性T细胞新亚群对HIV-1感染个体中病毒特异性T细胞免疫的影响。
对处于HIV-1疾病不同阶段的个体以及初次HIV感染后的个体进行纵向研究，定量检测其血浆中的HO-1蛋白水平。使用人类白细胞抗原（HLA）I类五聚体通过流式细胞术研究HO-1特异性CD8 T细胞。对经流式分选的HO-1特异性CD8 T细胞进行培养，并检测其对HIV-1特异性细胞毒性T细胞克隆的抑制活性。测定急性HIV-1感染个体分选的外周血单个核细胞（PBMC）亚群中的HO-1基因表达。
HIV-1感染时血浆HO-1水平显著升高，急性HIV-1感染个体中水平最高，且随时间逐渐下降。初次HIV-1感染的研究参与者中，HO-1特异性CD8 T细胞频率升高，经流式分选的HO-1特异性CD8 T细胞能够抑制HIV-1特异性细胞毒性T细胞克隆的裂解。急性HIV-1感染期间多个免疫细胞亚群中的HO-1基因表达上调，HO-1过表达在体外调节抗HIV免疫。
我们的数据表明，HO-1在急性HIV-1感染期间被诱导，可能介导抗炎作用并促使能够在体外抑制HIV-1特异性免疫反应的HO-1特异性CD8调节性T细胞扩增。对HO-1及本文所述新型CD8调节性细胞类型的研究为深入了解HIV-1感染中的免疫调节提供了进一步的见解，并可能为未来的免疫治疗干预带来潜力。
