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Rapid adaptation to human protein kinase R by a unique genomic rearrangement in rhesus cytomegalovirus

Cytomegaloviruses (CMVs) are generally unable to cross species barriers, in part because prolonged coevolution with one host species limits their ability to evade restriction factors in other species. However, the limitation in host range is incomplete. For example, rhesus CMV (RhCMV) can replicate...

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Autores principales: Child, Stephanie J., Greninger, Alexander L., Geballe, Adam P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864422/
https://www.ncbi.nlm.nih.gov/pubmed/33497413
http://dx.doi.org/10.1371/journal.ppat.1009088
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author Child, Stephanie J.
Greninger, Alexander L.
Geballe, Adam P.
author_facet Child, Stephanie J.
Greninger, Alexander L.
Geballe, Adam P.
author_sort Child, Stephanie J.
collection PubMed
description Cytomegaloviruses (CMVs) are generally unable to cross species barriers, in part because prolonged coevolution with one host species limits their ability to evade restriction factors in other species. However, the limitation in host range is incomplete. For example, rhesus CMV (RhCMV) can replicate in human cells, albeit much less efficiently than in rhesus cells. Previously we reported that the protein kinase R (PKR) antagonist encoded by RhCMV, rTRS1, has limited activity against human PKR but is nonetheless necessary and sufficient to enable RhCMV replication in human fibroblasts (HF). We now show that knockout of PKR in human cells or treatment with the eIF2B agonist ISRIB, which overcomes the translational inhibition resulting from PKR activation, augments RhCMV replication in HF, indicating that human PKR contributes to the inefficiency of RhCMV replication in HF. Serial passage of RhCMV in HF reproducibly selected for viruses with improved ability to replicate in human cells. The evolved viruses contain an inverted duplication of the terminal 6.8 kb of the genome, including rTRS1. The duplication replaces ~11.8 kb just downstream of an internal sequence element, pac1-like, which is very similar to the pac1 cleavage and packaging signal found near the terminus of the genome. Plaque-purified evolved viruses produced at least twice as much rTRS1 as the parental RhCMV and blocked the PKR pathway more effectively in HF. Southern blots revealed that unlike the parental RhCMV, viruses with the inverted duplication isomerize in a manner similar to HCMV and other herpesviruses that have internal repeat sequences. The apparent ease with which this duplication event occurs raises the possibility that the pac1-like site, which is conserved in Old World monkey CMV genomes, may serve a function in facilitating rapid adaptation to evolutionary obstacles.
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spelling pubmed-78644222021-02-12 Rapid adaptation to human protein kinase R by a unique genomic rearrangement in rhesus cytomegalovirus Child, Stephanie J. Greninger, Alexander L. Geballe, Adam P. PLoS Pathog Research Article Cytomegaloviruses (CMVs) are generally unable to cross species barriers, in part because prolonged coevolution with one host species limits their ability to evade restriction factors in other species. However, the limitation in host range is incomplete. For example, rhesus CMV (RhCMV) can replicate in human cells, albeit much less efficiently than in rhesus cells. Previously we reported that the protein kinase R (PKR) antagonist encoded by RhCMV, rTRS1, has limited activity against human PKR but is nonetheless necessary and sufficient to enable RhCMV replication in human fibroblasts (HF). We now show that knockout of PKR in human cells or treatment with the eIF2B agonist ISRIB, which overcomes the translational inhibition resulting from PKR activation, augments RhCMV replication in HF, indicating that human PKR contributes to the inefficiency of RhCMV replication in HF. Serial passage of RhCMV in HF reproducibly selected for viruses with improved ability to replicate in human cells. The evolved viruses contain an inverted duplication of the terminal 6.8 kb of the genome, including rTRS1. The duplication replaces ~11.8 kb just downstream of an internal sequence element, pac1-like, which is very similar to the pac1 cleavage and packaging signal found near the terminus of the genome. Plaque-purified evolved viruses produced at least twice as much rTRS1 as the parental RhCMV and blocked the PKR pathway more effectively in HF. Southern blots revealed that unlike the parental RhCMV, viruses with the inverted duplication isomerize in a manner similar to HCMV and other herpesviruses that have internal repeat sequences. The apparent ease with which this duplication event occurs raises the possibility that the pac1-like site, which is conserved in Old World monkey CMV genomes, may serve a function in facilitating rapid adaptation to evolutionary obstacles. Public Library of Science 2021-01-26 /pmc/articles/PMC7864422/ /pubmed/33497413 http://dx.doi.org/10.1371/journal.ppat.1009088 Text en © 2021 Child et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Child, Stephanie J.
Greninger, Alexander L.
Geballe, Adam P.
Rapid adaptation to human protein kinase R by a unique genomic rearrangement in rhesus cytomegalovirus
title Rapid adaptation to human protein kinase R by a unique genomic rearrangement in rhesus cytomegalovirus
title_full Rapid adaptation to human protein kinase R by a unique genomic rearrangement in rhesus cytomegalovirus
title_fullStr Rapid adaptation to human protein kinase R by a unique genomic rearrangement in rhesus cytomegalovirus
title_full_unstemmed Rapid adaptation to human protein kinase R by a unique genomic rearrangement in rhesus cytomegalovirus
title_short Rapid adaptation to human protein kinase R by a unique genomic rearrangement in rhesus cytomegalovirus
title_sort rapid adaptation to human protein kinase r by a unique genomic rearrangement in rhesus cytomegalovirus
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864422/
https://www.ncbi.nlm.nih.gov/pubmed/33497413
http://dx.doi.org/10.1371/journal.ppat.1009088
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