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Brief Definitive Reports

Robert P. Machold^*, Emmanuel J.H.J. Wiertz^*, Thomas R. Jones, and H.L. Ploegh^*

From the ^* Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; and Department of Molecular Biology, Infectious Diseases Section, Wyeth-Ayerst Research, Pearl River, New York 10965

Human cytomegalovirus downregulates the expression of human class I major histocompatibility complex (MHC) molecules by accelerating destruction of newly synthesized class I heavy chains. The HCMV genome contains at least two genes, US11 and US2, each of which encode a product sufficient for causing the dislocation of newly synthesized class I heavy chains from the lumen of the endoplasmic reticulum to the cytosol. Based on a comparison of their abilities to degrade the murine class I molecules H-2K^b, K^d, D^b, D^d, and L^d, the US11 and US2 gene products have non-identical specificities for class I molecules. Specifically, in human astrocytoma cells (U373-MG) transfected with the US11 gene, the K^b, D^b, D^d, and L^d molecules expressed via recombinant vaccinia virus are rapidly degraded, whereas in US2-transfected cells, only D^b and D^d are significantly destabilized. The diversity in HCMV-encoded functions that interfere with class I–restricted presentation likely evolved in response to the polymorphism of the MHC.

This work was supported by National Institutes of Health grants R01-AI33456 and R01-AI07463-17, and by Boehringer-Ingelheim.

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