NK cell activity during human cytomegalovirus infection is dominated by US2-11-mediated HLA class I down-regulation.
A highly attractive approach to investigate the influence and hierarchical organization of viral proteins on cellular immune responses is to employ mutant viruses carrying deletions of various virus-encoded, immune-modulating genes. Here, we introduce a novel set of deletion mutants of the human CMV (HCMV) lacking the UL40 region either alone or on the background of a deletion mutant devoid of the entire US2-11 region. Deletion of UL40 had no significant effect on lysis of infected cells by NK cells, indicating that the expected enhancement of HLA-E expression by specific peptides derived from HCMV-encoded gpUL40 leader sequences was insufficient to confer target cell protection. Moreover, the kinetics of MHC class I down-regulation by US2-11 genes observed at early and late phases postinfection with wild-type virus correlated with increased susceptibility to NK lysis. Thus, the influence of HCMV genes on NK reactivity follows a hierarchy dominated by the US2-11 region, which encodes all viral genes capable of down-modulating expression of classical and non-classical MHC class I molecules. The insights gained from studies of such virus mutants may impact on future therapeutic strategies and vaccine development and incorporate NK cells in the line of defense mechanisms against HCMV infection.
Falk
Christine S
CS
Institute of Molecular Immunology, GSF National Research Center for the Environment and Health, Munich, Germany.
Mach
Michael
M
Schendel
Dolores J
DJ
Weiss
Elisabeth H
EH
Hilgert
Ivan
I
Hahn
Gabriele
G
D000818:Animals; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000235:genetics / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D017353:Gene Deletion; D005814:Genes, Viral / Q000276:immunology; D006680:HLA Antigens / Q000096:biosynthesis*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D006801:Humans; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D051379:Mice; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D013045:Species Specificity; D014407:Tumor Cells, Cultured; D014759:Viral Envelope Proteins / Q000235:genetics / Q000502:physiology*; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*; D015678:Viral Structural Proteins / Q000235:genetics; D014774:Virulence
D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D016601:RNA-Binding Proteins; C074546:US11 protein, herpesvirus; C118670:US2 protein, Varicellovirus; C432877:US6 protein, Human cytomegalovirus; D014759:Viral Envelope Proteins; D014764:Viral Proteins; D015678:Viral Structural Proteins