Past and ongoing adaptation of human cytomegalovirus to its host: PLoS Pathogens

A. Mozzi, M. Biolatti, R. Cagliani, D. Forni, V. Dell’Oste, C. Pontremoli, C. Vantaggiato, U. Pozzoli, M. Clerici, S. Landolfo, M. Sironi

Research output: Contribution to journalArticlepeer-review

Abstract

Cytomegaloviruses (order Herpesvirales) display remarkable species-specificity as a result of long-term co-evolution with their mammalian hosts. Human cytomegalovirus (HCMV) is exquisitely adapted to our species and displays high genetic diversity. We leveraged information on inter-species divergence of primate-infecting cytomegaloviruses and intra-species diversity of clinical isolates to provide a genome-wide picture of HCMV adaptation across different time-frames. During adaptation to the human host, core viral genes were commonly targeted by positive selection. Functional characterization of adaptive mutations in the primase gene (UL70) indicated that selection favored amino acid replacements that decrease viral replication in human fibroblasts, suggesting evolution towards viral temperance. HCMV intra-species diversity was largely governed by immune system-driven selective pressure, with several adaptive variants located in antigenic domains. A significant excess of positively selected sites was also detected in the signal peptides (SPs) of viral proteins, indicating that, although they are removed from mature proteins, SPs can contribute to viral adaptation. Functional characterization of one of these SPs indicated that adaptive variants modulate the timing of cleavage by the signal peptidase and the dynamics of glycoprotein intracellular trafficking. We thus used evolutionary information to generate experimentally-testable hypotheses on the functional effect of HCMV genetic diversity and we define modulators of viral phenotypes. © 2020 Mozzi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Original languageEnglish
Article numbere1008476
Number of pages33
JournalPLoS Pathog.
Volume16
Issue number5
DOIs
Publication statusPublished - 2020

Keywords

  • signal peptidase
  • signal peptide
  • ARPE-19 cell line
  • Article
  • Catarrhini
  • cell migration
  • confocal microscopy
  • controlled study
  • CRL 2302 cell line
  • Cytomegalovirus
  • evolutionary adaptation
  • female
  • fibroblast
  • focus expansion assay
  • functional assessment
  • gene
  • gene mutation
  • gene sequence
  • genetic selection
  • genetic variability
  • growth competition assay
  • HEK293 cell line
  • HeLa cell line
  • human
  • human cell
  • male
  • molecular dynamics
  • molecular evolution
  • molecular genetics
  • mutagenesis
  • nonhuman
  • orthology
  • phenotype
  • protein interaction
  • retina pigment cell
  • SCRC 1041 cell line
  • sequence alignment
  • species difference
  • species diversity
  • UL70 gene
  • virus replication

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