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To evaluate the possible mechanisms used by SARS-CoV proteins to control NK cells activation, we considered that the activation of NK cells is partly controlled by the expression of HLA class molecules, via the interaction with specific NK cell receptors [38]. We evaluated the possible modification of surface HLA class I molecules on lung epithelial cells. The presentation of pathogen-derived peptides by HLA molecules and the genetic variability of HLA alleles in human populations account for their role in the individual responses to SARS-CoV-2 infection and/or progression. We showed that S1 protein on one side diminished classical HLA class I molecule expression but on the other side upregulated HLA-E expression. The protein HLA-E is a non-classical major histocompatibility complex molecule that binds peptides derived from a specific signal sequence [14]. We recognized an SP1-derived HLA-E binding peptide that might stabilize HLA-E expression on the surface of lung epithelial cells during SARS-CoV-2 infection. Interestingly, the highest affinity is demonstrated for the HLA-E*0101 allele. HLA-E surface expression conferred cell resistance to NK cell lysis, interacting with the NK cell inhibitory receptor CD94/NKG2A [14,38]. The involvement of HLA-E in the control of NK cell activation is confirmed also by the different results observed in K562 and lung cell models. K562 cells express no HLA molecules, providing no effective molecules to SARS-CoV spike 1 protein in order to control NK cells. For this, we observed IFN-gamma secretion and NK cell activation also in the presence of SARS-CoV spike 1 protein in the K562 cell model. On the contrary, lung cells, which express HLA-E molecules in the presence of SARS-CoV spike 1 protein, are able to inhibit IFN-gamma secretion and NK cell activation.