Infectious Disease and Immunodeficiency Section, Department of Internal Medicine 3, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Institute of Clinical and Molecular Virology, Universitätsklinikum Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
Front Immunol. 2021 Apr 28;12:627568. doi: 10.3389/fimmu.2021.627568. eCollection 2021.
The beta-coronavirus SARS-CoV-2 induces severe disease (COVID-19) mainly in elderly persons with risk factors, whereas the majority of patients experience a mild course of infection. As the circulating common cold coronaviruses OC43 and HKU1 share some homologous sequences with SARS-CoV-2, beta-coronavirus cross-reactive T-cell responses could influence the susceptibility to SARS-CoV-2 infection and the course of COVID-19. To investigate the role of beta-coronavirus cross-reactive T-cells, we analyzed the T-cell response against a 15 amino acid long peptide (SCoV-DP15: DLSPRWYFYYLGTGP) from the SARS-CoV-2 nucleoprotein sequence with a high homology to the corresponding sequence (QLLPRWYFYYLGTGP) in OC43 and HKU1. SCoV-DP15-specific T-cells were detected in 4 out of 23 (17.4%) SARS-CoV-2-seronegative healthy donors. As HIV-1 infection is a potential risk factor for COVID-19, we also studied a cohort of HIV-1-infected patients on antiretroviral therapy. 44 out of these 116 HIV-1-infected patients (37.9%) showed a specific recognition of the SCoV-DP15 peptide or of shorter peptides within SCoV-DP15 by CD4 T-cells and/or by CD8 T-cells. We could define several new cross-reactive HLA-I-restricted epitopes in the SARS-CoV-2 nucleoprotein such as SPRWYFYYL (HLA-B07, HLA-B35), DLSPRWYFYY (HLA-A02), LSPRWYFYY (HLA-A29), WYFYYLGTGP and WYFYYLGT. Epitope specific CD8 T-cell lines recognized corresponding epitopes within OC43 and HKU1 to a similar degree or even at lower peptide concentrations suggesting that they were induced by infection with OC43 or HKU1. Our results confirm that SARS-CoV-2-seronegative subjects can target SARS-CoV-2 not only by beta-coronavirus cross-reactive CD4 T-cells but also by cross-reactive CD8 cytotoxic T-cells (CTL). The delineation of cross-reactive T-cell epitopes contributes to an efficient epitope-specific immunomonitoring of SARS-CoV-2-specific T-cells. Further prospective studies are needed to prove a protective role of cross-reactive T-cells and their restricting HLA alleles for control of SARS-CoV-2 infection. The frequent observation of SARS-CoV-2-reactive T-cells in HIV-1-infected subjects could be a reason that treated HIV-1 infection does not seem to be a strong risk factor for the development of severe COVID-19.
β冠状病毒 SARS-CoV-2 主要在有风险因素的老年人群中引起严重疾病（COVID-19），而大多数患者经历轻度感染过程。由于循环的普通感冒冠状病毒 OC43 和 HKU1 与 SARS-CoV-2 有一些同源序列，β冠状病毒交叉反应性 T 细胞反应可能会影响 SARS-CoV-2 感染的易感性和 COVID-19 的病程。为了研究β冠状病毒交叉反应性 T 细胞的作用，我们分析了针对来自 SARS-CoV-2 核蛋白序列的 15 个氨基酸长肽（SCoV-DP15：DLSPRWYFYYLGTGP）的 T 细胞反应，该序列与 OC43 和 HKU1 中的相应序列（QLLPRWYFYYLGTGP）高度同源。在 23 名 SARS-CoV-2 血清阴性健康供体中，有 4 名（17.4%）检测到 SCoV-DP15 特异性 T 细胞。由于 HIV-1 感染是 COVID-19 的潜在危险因素，我们还研究了一组接受抗逆转录病毒治疗的 HIV-1 感染患者。在这些 116 名 HIV-1 感染患者中，有 44 名（37.9%）通过 CD4 T 细胞和/或 CD8 T 细胞特异性识别 SCoV-DP15 肽或 SCoV-DP15 内的较短肽。我们可以在 SARS-CoV-2 核蛋白中定义几个新的交叉反应性 HLA-I 限制性表位，例如 SPRWYFYYL（HLA-B07、HLA-B35）、DLSPRWYFYY（HLA-A02）、LSPRWYFYY（HLA-A29）、WYFYYLGTGP 和 WYFYYLGT。表位特异性 CD8 T 细胞系以相似的程度或甚至在较低的肽浓度下识别 OC43 和 HKU1 中的相应表位，提示它们是由 OC43 或 HKU1 感染诱导的。我们的结果证实，SARS-CoV-2 血清阴性的受试者不仅可以通过β冠状病毒交叉反应性 CD4 T 细胞，还可以通过交叉反应性 CD8 细胞毒性 T 细胞（CTL）靶向 SARS-CoV-2。交叉反应性 T 细胞表位的描绘有助于 SARS-CoV-2 特异性 T 细胞的有效表位特异性免疫监测。需要进一步的前瞻性研究来证明交叉反应性 T 细胞及其限制 HLA 等位基因对控制 SARS-CoV-2 感染的保护作用。在 HIV-1 感染患者中频繁观察到 SARS-CoV-2 反应性 T 细胞可能是一个原因，即治疗后的 HIV-1 感染似乎不是 COVID-19 发展的一个强烈危险因素。
