HUMAN CYTOMEGALOVIRUS DOWN-REGULATES HLA CLASS-I EXPRESSION BY REDUCING THE STABILITY OF CLASS-I H-CHAINS

Human CMV (HCMV) infection leads to an almost complete inhibition of expression of MHC class I proteins. After infection with HCMV, the biosynthesis of HLA class I molecules was examined in human lung fibroblasts and in mouse fibroblasts transfected with genes encoding the human class I H chain HLA-B27 and human beta2-microglobulin (beta2m). In both cell types, we observed a large decrease in steady state levels specific for human class I H chains-both free H chains and those complexed with beta2m. In the mouse cells transfected with HLA class I, infection did not affect levels and assembly of mouse class I H chains with human beta2m. The effect of HCMV infection on class I expression is insensitive to phosphonoacetic acid, suggesting the involvement of immediate early or early viral proteins. Pulse-chase analysis showed that the low steady state level of class I H chains in HCMV-infected cells is not the result of a reduced rate of synthesis. Rather, we observed accelerated degradation of class I H chains, regardless of their association with beta2m. We conclude that HCMV reduces human MHC class I protein levels by interference with the stability of class I H chains.