Klaus Früh, Ph.D.

Fig. 2: Viral interference with MHC class I presentation. Proteasomal degradation is circumvented in the case of the Epstein Barr Virus (EBV) protein EBNA-1 via a series of repetitive amino-acids. This mechanism prevents recognition of latently infected B cells since EBNA-1 is the only viral antigen expressed during the latent stage of EBV. The pp65 protein of Human Cytomegalovirus (HCMV) inhibits the proteasomal degradation of the immediate early protein IE1. Whereas these countermeasures are specific for given antigens, viruses have also developed means of blocking the processing of all peptides by inhibiting their translocation by the peptide transporter TAP. Herpes simplex virus expresses the short polypeptide ICP47 that binds to TAP and thus inhibits other peptides from binding and being translocated. In quite a different manner, the HCMV glycoprotein US6 inhibits peptide translocation by, but not binding to, TAP by an unknown mechanism. Other viral proteins act directly on the MHC class I molecule. The adenovirus glycoprotein E19 binds to newly synthesized MHC class I molecules and prevents their exit from the endoplasmic reticulum. Retention is achieved through the double-lysine motif in the cytoplasmic tail of E19 that binds to the cytosolic vesicle retrieval machinery of the cell. Both MCMV and HCMV express proteins, m152 and US3, respectively, that retain MHC class I molecules. However, they seem to act differently from E19, since the viral proteins are exported from the ER. Two other glycoproteins of HCMV, US2 and US3, not only retain MHC molecules but export them out of the ER back into the cytosol where they are degraded by the proteasome. The viral proteins thereby seem to accelerate a process that is generally responsible for disposing misfolded or incompletely assembled proteins from the lumen of the endoplasmic reticulum. The human immunodeficiency virus (HIV) protein vpu also achieves degradation of MHC class I but in a manner very different from US2 or US3 since vpu thus connects MHC I as well as CD4 to cellular proteasomal targeting system.

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