Efficient downregulation of major histocompatibility complex class I molecules in human epithelial cells infected with cytomegalovirus

Liver and intestinal epithelial cells are a major target of infection by cy tomegaloviruses (CMV), causing severe disease in affected organs of immunoc ompromised patients. CMV downregulates major histocompatibility complex cla ss 1 (MHC-1) molecule expression in fibroblasts in order to avoid lysis by CD8(+) cytotoxic T lymphocytes. However, MHC-1 expression in human cytomega lovirus (HCMV)-infected hepatic tissue was reported to be increased. As it is unclear at present whether HCMV affects MHC-1 expression in epithelial c ells, new cell culture models for HCMV infection of differentiated hepatobi liary cell lines were established. HCMV immediate early gene expression was achieved in 60 to 95% of cells. Progression of the HCMV replication cycle differed from prototypic infection of fibroblasts, since structural early a nd late proteins were produced at low levels and HCMV progeny yielded much lower titres in hepatobiliary cells. In contrast, HCMV glycoproteins, gpUS2 , gpUS3, gpUS6 and gpUS1 1, that downregulate MHC-1 expression were synthes ized with temporal kinetics and in a similar quantity to that seen in fibro blasts. As a result, HCMV infection led to a drastic and selective downregu lation of MHC-I expression in epithelial cells and was uniformly observed i rrespective of the hepatic or biliary origin of the cells. The new models d ocument for the first time a stealth function of HCMV in epithelial cells a nd indicate that the downregulation of MHC-1 expression by HCMV can occur i n the virtual absence of virus replication.