Human cytomegalovirus inhibits interferon-stimulated antiviral and immunoregulatory responses by disrupting Jak-Stat signal transduction: A novel mechanism of cytomegalovirus persistence

摘要

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus, which is able to persist for decades in its host. To facilitate the establishment of a persistent infection, HCMV has evolved protean countermeasures for anti-HCMV cellular immunity. The type I (IFN-$alpha/beta$) and type II (IFN-$gamma$) interferons represent a primordial, tightly regulated defense system against viral infection.;IFN-$alpha$ and IFN-$gamma$ stimulate the upregulation of genes with potent antiviral and immunoregulatory effects including MxA and 2$spprime$,5$spprime$-oligoadenylate synthetase (2$spprime$,5$spprime$-OAS) proteins, MHC class I and class II molecules, and components of antigen processing pathways. These IFN stimulated biological responses are mediated by a conserved signal transduction pathway consisting of the Janus kinase (Jaks) family of tyrosine kinases and transcription factors known as signal transducer and activator of transcription (Stats).;In this study, we demonstrate that both a clinical isolate and laboratory strain of HCMV inhibit IFN-$gamma$ inducible MHC class I and MHC class II expression in human endothelial cells and fibroblasts. Electrophoretic mobility shift assays reveal a defect in IFN-$gamma$ signal transduction resulting from direct HCMV/cell interactions. Immunoprecipitation experiments demonstrate a striking decrease in Jak1 levels in HCMV infected cells possibly mediated by a HCMV-associated enhancement of Jak1 protein degradation.;Similar analyses of IFN-$alpha$ stimulated responses show that HCMV inhibits IFN-$alpha$ stimulated MHC class I, interferon regulatory factor-1 (IRF-1), MxA, and 2$spprime,5spprime$-OAS gene expression, transcription factor activation, and signal transduction in infected fibroblasts and endothelial cells. Immunoprecipitation and immunoblotting experiments show that these defects are associated with downregulation of Jak1 and p48 expression, required components of the IFN-$alpha$ signal transduction pathway.;This is the first report that a member of the herpesvirus family globally blocks IFN stimulated antiviral and immunoregulatory responses. Moreover, this is the first report of a direct virus-associated alteration in Jak levels. These findings represent a paradigm shift in understanding HCMV/immune system interactions. We propose that this novel immune escape mechanism is a major means by which HCMV is capable of escaping host immunity and establishing persistence and may lead to the identification of HCMV gene products that would aid in the development of vaccines or novel therapies for HCMV associated disease.