MERS-CoV and H5N1 influenza virus antagonize antigen presentation by altering the epigenetic landscape

Menachery, Vineet D.; Schäfer, Alexandra; Burnum-Johnson, Kristin E.; Mitchell, Hugh D.; Eisfeld, Amie J.; Walters, Kevin B.; Nicora, Carrie D.; Purvine, Samuel O.; Casey, Cameron P.; Monroe, Matthew E.; Weitz, Karl K.; Stratton, Kelly G.; Webb-Robertson, Bobbie-Jo M.; Gralinski, Lisa E.; Metz, Thomas O.; Smith, Richard D.; Waters, Katrina M.; Sims, Amy C.; Kawaoka, Yoshihiro; Baric, Ralph S.

CoV infection suggested that a nonconserved portion of the MERS-CoV backbone is involved. With this in mind, we focused on the MERS-CoV accessory ORF proteins, which have limited sequence similarities with other CoV family proteins. Using a previously described MERS-CoV mutant that deletes all four accessory ORFs (d3-5) (15), we infected Calu3 cells and examined both viral replication and proteomics. Following infection, the d3-5 mutant virus produced robust attenuation in terms of viral replication (Fig. S3B) . However, despite a nearly 100-fold reduction in viral replication, the d3-5 mutant viruses maintained strong down-regulation of MHC class I molecules HLA-A and -C ( Fig. 6 C and D) . While not equivalent to WT MERS-CoV down-regulation, the d3-5 mutant maintained lower absolute MHC class I peptide abundance compared with WT H5N1-VN1203 ( Fig. 6 A and B) . Together, the data suggest that even a robustly attenuated MERS-CoV mutant can stimulate down-regulation of antigen-presentation molecules and potentially implicate host processes in contributing to reduction of MHC class I molecules following infection.