Human cytomegalovirus inhibits IFN-alpha-stimulated antiviral and immunoregulatory responses by blocking multiple levels of IFN-alpha signal transduction

The type I IFNs represent a primordial, tightly regulated defense system ag ainst acute viral infection. IFN-alpha confers resistance to viral infectio n by activating a conserved signal transduction pathway that up-regulates d irect antiviral effecters and induces immunomodulatory activities. Given th e critical role of IFN-alpha in anti-human cytomegalovirus. (HCMV) immunity and the profound ability of HCMV to escape the host immune response, we hy pothesized that HCMV blocks IFN-alpha-stimulated responses by disrupting mu ltiple levels of the IFN-alpha signal transduction pathway. We demonstrate that HCMV inhibits IFN-alpha-stimulated MHC class I, IFN regulatory factor- 1, MxA and 2',5-oligoadenylate synthetase gene expression, transcription fa ctor activation, and signaling in infected fibroblasts and endothelial cell s by decreasing the expression of Janus kinase 1 and p48, two essential com ponents of the IFN-alpha signal transduction pathway. This investigation is the first to report inhibition of type I IFN signaling by a herpesvirus, W e propose that this novel immune escape mechanism is a major means by which HCMV is capable of escaping host immunity and establishing persistence.