Cutting edge: The human cytomegalovirus UL40 gene product contains a ligand for HLA-E and prevents NK cell-mediated lysis

Human CMV has evolved multiple strategies to interfere with immune recognit ion of the host. A variety of mechanisms target Ag presentation by MHC clas s I molecules resulting in a reduced class I cell-surface expression, This down-regulation of class I molecules is expected to trigger NK cytotoxicity , which would have to be counteracted by the virus to establish long-term i nfection. Here we describe that the human CMV open reading frame UL40 encod es a canonical ligand for HLA-E, identical with the HLA-Cw03 signal sequenc e-derived peptide. Expression of UL40 in HLA-E-positive target cells confer red resistance to NK cell lysis via the CD94/NKG2A receptor. Generation of the UL40-derived HLA-E ligand was also observed in TAP-deficient cells, The presence of a functional TAP-independent HLA-E ligand in the UL40 signal s equence implicates this viral gene as an important negative regulator of NK activity.