Human cytomegalovirus protein US6 inhibits the transporter associated with antigen processing (TAP), which transports peptides into the endoplasmic reticulum (ER) for binding to major histocompatibility complex (MHC) class I molecules. We demonstrate that, in TAP-deficient cells, US6 is retained in the ER and binds to calnexin, but does not inhibit cell-surface expression of HLA-A201, an MHC class I allele that binds to peptides whose import into the ER is TAP-independent. Furthermore, in TAP-positive cells, US6 reduces the cell-surface expression of HLA-B2705, an MHC class I allele that is dependent on TAP for peptide binding, to a greater extent than that of HLA-A201. These data demonstrate that US6 has differential effects on the cell-surface expression of MHC class I alleles and are consistent with TAP being the sole inhibitory target of US6 in the MHC class I antigen-presentation pathway.


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