Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany
Liane Bauersfeld
Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany
Ivo Schirmeister
Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany
Chiara Noemi-Marie Mireisz
Rudolf Virchow Center, Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany
Valerie Oberhardt
Faculty of Medicine, University of Freiburg, Freiburg, Germany; Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Medical Center University of Freiburg, Freiburg, Germany
Lea Mery
Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany
Di Wu
Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany
Christopher Sebastian Jürges
Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany
Robbert M Spaapen
Department of Immunopathology, Sanquin Research, Amsterdam, Netherlands; Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
Claudio Mussolino
Faculty of Medicine, University of Freiburg, Freiburg, Germany; Institute for Transfusion Medicine and Gene Therapy, Medical Center University of Freiburg, Freiburg, Germany; Center for Chronic Immunodeficiency, Medical Center University of Freiburg, Freiburg, Germany
Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; Institute for the Research on HIV and AIDS-associated Diseases, University Hospital Essen, Essen, Germany
Lars Dölken
Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany; Institute of Virology, Hannover Medical School, Hannover, Germany
Wolfgang Paster
St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
Florian Erhard
Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany
Maike Hofmann
Faculty of Medicine, University of Freiburg, Freiburg, Germany; Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Medical Center University of Freiburg, Freiburg, Germany
Andreas Schlosser
Rudolf Virchow Center, Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany
Faculty of Medicine, University of Freiburg, Freiburg, Germany
Frank Momburg
Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Center, National Center for Tumor Diseases (NCT), Heidelberg University Hospital, Heidelberg, Germany
Human leucocyte antigen class I (HLA-I) molecules play a central role for both NK and T-cell responses that prevent serious human cytomegalovirus (HCMV) disease. To create opportunities for viral spread, several HCMV-encoded immunoevasins employ diverse strategies to target HLA-I. Among these, the glycoprotein US10 is so far insufficiently studied. While it was reported that US10 interferes with HLA-G expression, its ability to manipulate classical HLA-I antigen presentation remains unknown. In this study, we demonstrate that US10 recognizes and binds to all HLA-I (HLA-A, -B, -C, -E, -G) heavy chains. Additionally, impaired recruitment of HLA-I to the peptide loading complex was observed. Notably, the associated effects varied significantly dependending on HLA-I genotype and allotype: (i) HLA-A molecules evaded downregulation by US10, (ii) tapasin-dependent HLA-B molecules showed impaired maturation and cell surface expression, and (iii) β2m-assembled HLA-C, in particular HLA-C*05:01 and -C*12:03, and HLA-G were strongly retained in complex with US10 in the endoplasmic reticulum. These genotype-specific effects on HLA-I were confirmed through unbiased HLA-I ligandome analyses. Furthermore, in HCMV-infected fibroblasts inhibition of overlapping US10 and US11 transcription had little effect on HLA-A, but induced HLA-B antigen presentation. Thus, the US10-mediated impact on HLA-I results in multiple geno- and allotypic effects in a so far unparalleled and multimodal manner.
