MHC class I - Subversive gene functions of cytomegalovirus and their regulation by interferons - an intricate balance

Multiple glycoproteins of human cytomegalovirus (HCMV) encoded by the genes US2, US3, US6 and US11 interrupt the MHC class I pathway of antigen presentation at distinct checkpoints to avoid recognition of infected cells by cytotoxic CD8+ T lymphocytes. The action of cytokines like interferon (IFN)-gamma, IFN-alpha/beta and tumour necrosis factor alpha (TNF-alpha) compensate for the viral inhibition and restore antigen presentation in HCMV-infected cells. This finding was explained by their effects on cellular rather than viral genes and reflected by an increase in the production, assembly and maturation of MHC class I molecules resulting in an escape of MHC I from viral control. Here we reproduce the IFN-gamma-mediated effect when MHC I-subversive gene functions of HCMV are tested in isolation, but the efficacy of IFN-gamma to restore MHC I surface expression in US2-, US6- and US11-transfectants differs significantly. In addition, in HCMV-infected cells IFN-gamma strongly affects the synthesis of the US6-encoded glycoprotein. Despite the capability of HCMV to block the interferon signaling pathway the IFN-gamma driven enhancement of MHC class I and class II expression remains effective provided that cells are exposed to IFN-gamma before infection. Our findings illustrate a complex interplay between host immune factors and viral immune evasion functions.