SARS-CoV-2 NSP5 Antagonizes the MHC II Antigen Presentation Pathway by Hijacking Histone Deacetylase 2

The clearance of SARS-CoV-2 requires a multi-faceted immune response that is initiated by innate immune cells, with infection ultimately resolved by adaptive immune mechanisms. Induction of adaptive immunity to SARS-CoV-2 is dependent on the presentation of viral antigens on MHC II by professional antigen presenting cells such as dendritic cells and macrophages, to induce robust activation of CD4+ T cells. SARS-CoV-2 interferes with antigen presentation by downregulating MHC II on the antigen presenting cells of COVID-19 patients, but the molecular mechanism mediating this process is unelucidated. In this study, analysis of protein and gene expression in human antigen presenting cells reveals that the expression of MHC II is inhibited by the SARS-CoV-2 main protease, NSP5. Suppression of MHC II expression occurs via downregulation of the transcription factor CIITA, which is required for MHC II expression. This downregulation of CIITA is independent of NSP5's proteolytic activity, and rather, NSP5 delivers HDAC2 to the CIITA promoter via interactions with IRF3, Here, HDAC2 deacetylates and inactivates the CIITA promoter. This loss of CIITA expression prevents further expression of MHC II, with this suppression alleviated by ectopic expression of CIITA or knockdown of HDAC2. These results identify a novel mechanism by which SARS-CoV-2 can limit antigen presentation on MHC II, thereby delaying or weakening the subsequent adaptive immune response. ### Competing Interest Statement The authors have declared no competing interest.