TY  - JOUR
AU  - Zimmermann, Cosima
AU  - Watson, Gabrielle M
AU  - Bauersfeld, Liane
AU  - Berry, Richard
AU  - Ciblis, Barbara
AU  - Lan, Huan
AU  - Gerke, Carolin
AU  - Oberhardt, Valerie
AU  - Fuchs, Jonas
AU  - Hofmann, Maike
AU  - Freund, Christian
AU  - Rossjohn, Jamie
AU  - Momburg, Frank
AU  - Hengel, Hartmut
AU  - Halenius, Anne
TI  - Diverse cytomegalovirus US11 antagonism and MHC-A evasion strategies reveal a tit-for-tat coevolutionary arms race in hominids.
JO  - Proceedings of the National Academy of Sciences of the United States of America
VL  - 121
IS  - 9
SN  - 0027-8424
CY  - Washington, DC
PB  - National Acad. of Sciences
M1  - DKFZ-2024-00379
SP  - e2315985121
PY  - 2024
AB  - Recurrent, ancient arms races between viruses and hosts have shaped both host immunological defense strategies as well as viral countermeasures. One such battle is waged by the glycoprotein US11 encoded by the persisting human cytomegalovirus. US11 mediates degradation of major histocompatibility class I (MHC-I) molecules to prevent CD8+ T-cell activation. Here, we studied the consequences of the arms race between US11 and primate MHC-A proteins, leading us to uncover a tit-for-tat coevolution and its impact on MHC-A diversification. We found that US11 spurred MHC-A adaptation to evade viral antagonism: In an ancestor of great apes, the MHC-A A2 lineage acquired a Pro184Ala mutation, which confers resistance against the ancestral US11 targeting strategy. In response, US11 deployed a unique low-complexity region (LCR), which exploits the MHC-I peptide loading complex to target the MHC-A2 peptide-binding groove. In addition, the global spread of the human HLA-A*02 allelic family prompted US11 to employ a superior LCR strategy with an optimally fitting peptide mimetic that specifically antagonizes HLA-A*02. Thus, despite cytomegaloviruses low pathogenic potential, the increasing commitment of US11 to MHC-A has significantly promoted diversification of MHC-A in hominids.
KW  - HLA-A (Other)
KW  - MHC class I (Other)
KW  - coevolution (Other)
KW  - cytomegalovirus (Other)
KW  - tapasin (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:38377192
DO  - DOI:10.1073/pnas.2315985121
UR  - https://inrepo02.dkfz.de/record/288506
ER  -