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J. Exp. Med.,
Volume 187, Number 5, March 2, 1998 675-683
By
From the * Department of Pathology, The Ohio State University, Columbus, Ohio 43210; Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that is able to persist for decades
in its host. HCMV has evolved protean countermeasures for anti-HCMV cellular immunity
that facilitate establishment of persistence. Recently it has been shown that HCMV inhibits interferon Department of Microbiology and Immunology, Emory University, Atlanta, Georgia 30322; and § Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210
(IFN-)-stimulated MHC class II expression, but the mechanism for this effect is
unknown. IFN- signal transduction (Jak/Stat pathway) and class II transactivator (CIITA) are
required components for IFN--stimulated MHC class II expression. In this study, we demonstrate that both a clinical isolate and a laboratory strain of HCMV inhibit inducible MHC class
II expression at the cell surface and at RNA level in human endothelial cells and fibroblasts. Moreover, reverse transcriptase polymerase chain reaction and Northern blot analyses demonstrate that neither CIITA nor interferon regulatory factor 1 are upregulated in infected cells.
Electrophoretic mobility shift assays reveal a defect in IFN- signal transduction, which was
shown by immunoprecipitation to be associated with a striking decrease in Janus kinase 1 (Jak1)
levels. Proteasome inhibitor studies with carboxybenzyl-leucyl-leucyl-leucine vinyl sulfone
suggest an HCMV-associated enhancement of Jak1 protein degradation. This is the first report
of a mechanism for the HCMV-mediated disruption of inducible MHC class II expression and
a direct virus-associated alteration in Janus kinase levels. These findings are yet another example
of the diverse mechanisms by which HCMV avoids immunosurveillance and establishes persistence.
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