A Class l-restricted I cell response deployed against avirus-infectedcell constitutes a formidable selective pressure on the pathogen. To escape immune detection, the Herpesviruses have evolved and perfected a number of post-translational strategies to avoid antigen presentation via Class I molecules. A fuller understanding of how viruses manage to escape from the immune system should help us understand better the mechanistic and functional iaspects of antigen presentation. We should be able to exoloit this information not only to design better strategies for anti viral therapies, but we could perhaps also learn from these viruses how to avoid and unwanted attack by T cells as a,nadjunct to organ transplantation or gene therapy. The present proposal will address, using biochemical, cell- biological and immunological methods,a number of key aspects of Class I restricted antigen presentation. First, we shall develop novel pharmacological tools with which to manipulate cytosolic proteolysis, and explore proteolytic pathways that manifest themselves when proteasomes are inactivated by active-site directed covalent inhibitors. Second, we shall exploit the occurrence of a natural inhibitor of the MHC-eicoded peptide transporter, TAP, to explore how the Herpes Simplex Virus manages to escape the detection of cytotoxic T cells. The protein responsible for this evasion, ICP47, has been produced through complete synthesis and offers a well-nigh-ideal target for detailed structure-function analysis through a peptide-synthetic approach. The stable membrane insertion or assembly of MHC class I molecules is targeted by HCMV through expression of the US2 and US11 gene products. These proteins catalyze a reaction in which newly synthesized Class I molecules are dislocated for the ER
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