Human cytomegalovirus inhibits major histocompatibility complex class II expression by disruption of the Jak/Stat pathway

Daniel M. Miller, Brian M. Rahill, Jeremy M. Boss, Michael Dale Lairmore, Joan E. Durbin, W. James Waldman, Daniel D. Sedmak

Research output: Contribution to journalArticle

273 Scopus citations

Abstract

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 in terferon γ (IFN-γ)- stimulated MHC class II expression, but the mechanism for this effect is unknown. IFN-γ signal transduction (Jak/Stat pathway) and class II transactivator (CIITA) are required components for IFN-γ-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-γ signal transduction, which was shown inmunoprecipitation 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 which HCMV avoids immunosurveillance and establishes persistence.

Original languageEnglish (US)
Pages (from-to)675-683
Number of pages9
JournalJournal of Experimental Medicine
Volume187
Issue number5
DOIs
StatePublished - Mar 2 1998
Externally publishedYes

ASJC Scopus subject areas

  • Immunology

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