MECHANISM OF MCMV's INHIBITION OF ANTIGEN PRESENTATION

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DESCRIPTION (provided by the applicant): Many herpes viruses encode proteins that disrupt the MHC class I pathway of antigen processing; these genes offer insights into basic immunological and cell biological processes, and provide new tools for immunological investigation and potentially therapeutics. Murine cytomegalovirus (MCMV) offers a unique opportunity to understand how these genes function and their impact on the immune system in the host with which they have co-evolved for tens of millions of years. Two MCMV genes (m6 and ml 52) have been shown to interfere with antigen processing. Evidence is presented that a third gene, m4, also interferes with antigen presentation. m4 is unique amongst viral immune evasion genes in that it does not alter the trafficking pattern of class I molecules. Its product, m4gp34, is primarily found in the ER, where it interacts extensively with class I. A small portion of m4gp34 forms a different, detergent stable complex with class I and travels with it to the cell surface where they remain tightly associated. The goal of this project is to identify the molecular mechanism whereby m4gp34 inhibits antigen presentation. Recombinant MCMV expressing ova wilt be established to enable the effect of m4gp34 on class I loaded with specific antigenic peptide to be followed. These will be used to determine, firstly, whether m4gp34 acts at the cell surface to inhibit the ability of the class 1-peptide complex to engage its receptor or co-receptor and transmit an activating signal to CTL; and secondly, whether m4gp34 in the ER interferes with the ability of Kb molecules to acquire antigenic peptide.