Escape of human cytomegalovirus from HLA-DR-restricted CD4(+) T-cell response is mediated by repression of gamma interferon-induced class II transactivator expression

Human cytomegalovirus (HCMV), a betaherpesvirus, is a pathogen which escape s immune recognition through various mechanisms. In this paper, we show tha t HCMV down regulates gamma interferon (IFN-gamma)-induced HLA-DR expressio n in U373 MG astrocytoma cells due to a defect downstream of STAT1 phosphor ylation and nuclear translocation. Repression of class II transactivator (C IITA) mRNA expression is detected within the first hours of IFN-gamma-HCMV coincubation and results in the absence of HLA-DR synthesis. This defect le ads to the absence of presentation of the major immediate-early protein IE1 to specific CD4(+) T-cell clones when U373 MG cells, used as antigen-prese nting cells, are treated with IFN-gamma plus HCMV. However, presentation of endogenously synthesized IE1 can be restored when U373 MG cells are transf ected with CIITA prior to infection with HCMV. Altogether, the data indicat e that the defect induced by HCMV resides in the activation of the IFN-gamm a-responsive promoter of CIITA, This is the first demonstration of a viral inhibition of CIITA expression.