The Journal of Experimental Medicine
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Published 16 September 2002. doi:10.1084/jem.20020811
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© Rockefeller University Press, 0022-1007/2002/9/805/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 6, September 16, 2002 805-816

Major Histocompatibility Complex Class I Allele-specific Cooperative and Competitive Interactions between Immune Evasion Proteins of Cytomegalovirus

Markus Wagner1, Anja Gutermann1, Jürgen Podlech2, Matthias J. Reddehase2 and Ulrich H. Koszinowski1

1 Max von Pettenkofer Institute, Department for Virology, Ludwig-Maximilians-Universität München, 80336 Munich, Germany
2 Institute for Virology, Johannes Gutenberg-Universität, 55101 Mainz, Germany

Address correspondence to U.H. Koszinowski, Max von Pettenkofer Institute, Pettenkoferstr 9a, 80336 Munich, Germany. Phone: 49-89-5160-5290; Fax: 49-89-5160-5292; E-mail: koszinowski{at}m3401.mpk.med.uni-muenchen.de

Cytomegaloviruses (CMVs) deploy a set of genes for interference with antigen presentation in the major histocompatibility complex (MHC) class I pathway. In murine CMV (MCMV), three genes were identified so far: m04/gp34, m06/gp48, and m152/gp40. While their function as immunoevasins was originally defined after their selective expression, this may not necessarily reflect their biological role during infection. The three immunoevasins might act synergistically, but they might also compete for their common substrate, the MHC class I complexes. To approach this question in a systematic manner, we have generated a complete set of mutant viruses with deletions of the three genes in all seven possible combinations. Surface expression of a set of MHC class I molecules specified by haplotypes H-2d (Kd, Dd, and Ld) and H-2b (Kb and Db) was the parameter for evaluation of the interference with class I trafficking. The data show the following: first, there exists no additional MCMV gene of major influence on MHC class I surface expression; second, the strength of the inhibitory effect of immunoevasins shows an allele-specific hierarchy; and third, the immunoevasins act not only synergistically but can, in certain combinations, interact antagonistically. In essence, this work highlights the importance of studying the immunosubversive mechanisms of cytomegaloviruses in the context of gene expression during the viral replicative cycle in infected cells.

Key Words: murine cytomegalovirus • BAC • immune evasion • MHC class II • allele


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