Diverse cytomegalovirus US11 antagonism and MHC-A evasion strategies reveal a tit-for-tat coevolutionary arms race in hominids

Zimmermann, Cosima, Watson, Gabrielle M., Bauersfeld, Liane, Berry, Richard, Ciblis, Barbara, Lan, Huan, Gerke, Carolin, Oberhardt, Valerie, Fuchs, Jonas, Hofmann, Maike, Freund, Christian, Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, Momburg, Frank, Hengel, Hartmut and Halenius, Anne 2024. Diverse cytomegalovirus US11 antagonism and MHC-A evasion strategies reveal a tit-for-tat coevolutionary arms race in hominids. Proceedings of the National Academy of Sciences 121 (9) , e2315985121. 10.1073/pnas.2315985121

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Abstract

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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: https://creativecommons.org/licenses/by-nc-nd/4.0/, Start Date: 2024-02-20
Publisher:	National Academy of Sciences
ISSN:	0027-8424
Date of First Compliant Deposit:	21 November 2024
Date of Acceptance:	10 January 2024
Last Modified:	09 Dec 2024 16:32
URI:	https://orca.cardiff.ac.uk/id/eprint/174197

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