Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; Institute for Experimental Cellular Therapy, University Hospital Essen, University of Duisburg-Essen, Essen, 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, University of Duisburg-Essen, Essen, Germany
Institute for Experimental Cellular Therapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Thilo Bracht
Medizinisches Proteom Center, Ruhr University Bochum, Bochum, Germany; Department of Anesthesia, Intensive Care Medicine and Pain Therapy, University Hospital Knappschaftskrankenhaus Bochum, Bochum, Germany
Medizinisches Proteom Center, Ruhr University Bochum, Bochum, Germany; Department of Anesthesia, Intensive Care Medicine and Pain Therapy, University Hospital Knappschaftskrankenhaus Bochum, Bochum, Germany
Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Tanja Becker
Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Denise Mennerich
Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Sebastian Voigt
Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Lori Frappier
Department of Molecular Genetics, University of Toronto, Toronto, Canada
Barbara Sitek
Medizinisches Proteom Center, Ruhr University Bochum, Bochum, Germany; Department of Anesthesia, Intensive Care Medicine and Pain Therapy, University Hospital Knappschaftskrankenhaus Bochum, Bochum, Germany
Katharina Fleischhauer
Institute for Experimental Cellular Therapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Heidelberg, 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, University of Duisburg-Essen, Essen, Germany
Human cytomegalovirus (HCMV) is a relevant pathogen, especially for individuals with impaired immunity. Harnessing potent immune antagonists, HCMV circumvents sterile immunity. Given that HCMV prevents the upregulation of human leukocyte antigen (HLA)-DP and HLA-DR, we screened a library of HCMV genes by co-expression with the HLA class II (HLA-II)-inducing transcription coordinator class II transactivator (CIITA). We identified the latency regulator pUS28 as an interaction factor and potent viral antagonist of CIITA-driven expression of CD74, HLA-DR, HLA-DM, HLA-DQ, and HLA-DP. Both wt-pUS28 and a mutant incapable of inducing G protein-coupled signaling (R129A), but not a mutant lacking the C-terminus, drastically reduced the CIITA protein abundance post-transcriptionally. While control CD4 + T cells from HCMV-seropositive individuals vigorously responded to CIITA-expressing cells decorated with HCMV antigens, pUS28 expression was sufficient to inhibit HLA-II induction and immune recognition by HCMV-specific CD4 + T cells. Our data uncover pUS28 to be employed by HCMV to evade HLA-II-mediated recognition by CD4 + T cells.
