The ORF8 protein of SARS-CoV-2 mediates immune evasion through down-regulating MHC-Ι

Zhang, Yiwen; Chen, Yingshi; Li, Yuzhuang; Huang, Feng; Luo, Baohong; Yuan, Yaochang; Xia, Baijin; Ma, Xiancai; Yang, Tao; Yu, Fei; Liu, Jun; Liu, Bingfeng; Song, Zheng; Chen, Jingliang; Yan, Shumei; Wu, Liyang; Pan, Ting; Zhang, Xu; Li, Rong; Huang, Wenjing; He, Xin; Xiao, Fei; Zhang, Junsong; Zhang, Hui

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic and has claimed over 2 million lives worldwide. Although the genetic sequences of SARS-CoV and SARS-CoV-2 have high homology, the clinical and pathological characteristics of COVID-19 differ significantly from those of SARS. How and whether SARS-CoV-2 evades (cellular) immune surveillance requires further elucidation. In this study, we show that SARS-CoV-2 infection leads to major histocompability complex class Ι (MHC-Ι) down-regulation both in vitro and in vivo. The viral protein encoded by open reading frame 8 (ORF8) of SARS-CoV-2, which shares the least homology with SARS-CoV among all viral proteins, directly interacts with MHC-Ι molecules and mediates their down-regulation. In ORF8-expressing cells, MHC-Ι molecules are selectively targeted for lysosomal degradation via autophagy. Thus, SARS-CoV-2–infected cells are much less sensitive to lysis by cytotoxic T lymphocytes. Because ORF8 protein impairs the antigen presentation system, inhibition of ORF8 could be a strategy to improve immune surveillance.