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The Murine Cytomegalovirus Immune Evasion Protein m4/gp34 Forms Biochemically Distinct Complexes with Class I MHC at the Cell Surface and in a Pre-Golgi Compartment¹

Daniel G. Kavanagh^*, Ulrich H. Koszinowski and Ann B. Hill^2,*

^* Department of Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland, OR 97201; and Max von Pettenkofer Institut, Munich, Germany

We have recently demonstrated that the murine CMV (MCMV) gene m4 is an immune evasion gene that protects MCMV-infected targets from some virus-specific CTL clones. m4 encodes m4/gp34, a 34-kDa glycoprotein that binds to major histocompatibility complex class I in the endoplasmic reticulum and forms a detergent-stable complex that is exported to the surface of the cell. To investigate how m4/gp34 promotes CTL evasion, we analyzed the assembly and export of m4/gp34-K^b complexes. We found that 50–70% of K^b exported over the course of MCMV infection was m4/gp34 associated. Because these complexes are present at the cell surface, it is possible that m4 mediates CTL evasion by interfering with contact between class I and receptors on the T cell. In addition, we found that K^b retained by the MCMV immune evasion gene m152 formed a novel type of complex with Endo H-sensitive m4/gp34; these complexes are distinguished from the exported complexes by being stable in 1% digitonin and unstable in 1% Nonidet P-40. Because this association occurs in a pre-Golgi compartment, m4/gp34 might also interfere with Ag presentation by affecting some aspect of class I assembly, such as peptide loading. Although m4/gp34 requires ₂-microglobulin to bind class I, there was no significant binding of m4/gp34 to ₂-microglobulin in the absence of class I H chain, demonstrating that m4/gp34 forms Nonidet P-40-stable complexes specifically with folded conformations of class I. We conclude that m4/gp34 promotes immune evasion by a novel mechanism involving altered assembly and/or T cell recognition of class I molecules.

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