HLA-B locus products resist degradation by the human cytomegalovirus immunoevasin US11.

To escape CD8+ T-cell immunity， human cytomegalovirus (HCMV) US11 redirects MHC-I for rapid ER-associated proteolytic degradation (ERAD). In humans， classical MHC-I molecules are encoded by the highly polymorphic HLA-A， -B and -C gene loci. While HLA-C resists US11 degradation， the specificity for HLA-A and HLA-B products has not been systematically studied. In this study we analyzed the MHC-I peptide ligands in HCMV-infected cells. A US11-dependent loss of HLA-A ligands was observed， but not of HLA-B. We revealed a general ability of HLA-B to assemble with β2m and exit from the ER in the presence of US11. Surprisingly， a low-complexity region between the signal peptide sequence and the Ig-like domain of US11， was necessary to form a stable interaction with assembled MHC-I and， moreover， this region was also responsible for changing the pool of HLA-B ligands. Our data suggest a two-pronged strategy by US11 to escape CD8+ T-cell immunity， firstly， by degrading HLA-A molecules， and secondly， by manipulating the HLA-B ligandome.