Strategy of Human Cytomegalovirus To Escape Interferon Beta-Induced APOBEC3G Editing Activity

Sara Pautasso, Ganna Galitska, Valentina Dell'Oste, Matteo Biolatti, Rachele Cagliani, Diego Forni, Marco De Andrea, Marisa Gariglio, Manuela Sironi, Santo Landolfo

Research output: Contribution to journalArticle

Abstract

The apolipoprotein B editing enzyme catalytic subunit 3 (APOBEC3) is a family of DNA cytosine deaminases that mutate and inactivate viral genomes by single-strand DNA editing, thus providing an innate immune response against a wide range of DNA and RNA viruses. In particular, APOBEC3A (A3A), a member of the APOBEC3 family, is induced by human cytomegalovirus (HCMV) in decidual tissues where it efficiently restricts HCMV replication, thereby acting as an intrinsic innate immune effector at the maternal-fetal interface. However, the widespread incidence of congenital HCMV infection implies that HCMV has evolved to counteract APOBEC3-induced mutagenesis through mechanisms that still remain to be fully established. Here, we have assessed gene expression and deaminase activity of various APOBEC3 gene family members in HCMV-infected primary human foreskin fibroblasts (HFFs). Specifically, we show that APOBEC3G (A3G) gene products and, to a lesser degree, those of A3F but not of A3A, are upregulated in HCMV-infected HFFs. We also show that HCMV-mediated induction of A3G expression is mediated by interferon beta (IFN-β), which is produced early during HCMV infection. However, knockout or overexpression of A3G does not affect HCMV replication, indicating that A3G is not a restriction factor for HCMV. Finally, through a bioinformatics approach, we show that HCMV has evolved mutational robustness against IFN-β by limiting the presence of A3G hot spots in essential open reading frames (ORFs) of its genome. Overall, our findings uncover a novel immune evasion strategy by HCMV with profound implications for HCMV infections.IMPORTANCE APOBEC3 family of proteins plays a pivotal role in intrinsic immunity defense mechanisms against multiple viral infections, including retroviruses, through the deamination activity. However, the currently available data on APOBEC3 editing mechanisms upon HCMV infection remain unclear. In the present study, we show that particularly the APOBEC3G (A3G) member of the deaminase family is strongly induced upon infection with HCMV in fibroblasts and that its upregulation is mediated by IFN-β. Furthermore, we were able to demonstrate that neither A3G knockout nor A3G overexpression appears to modulate HCMV replication, indicating that A3G does not inhibit HCMV replication. This may be explained by HCMV escape strategy from A3G activity through depletion of the preferred nucleotide motifs (hot spots) from its genome. The results may shed light on antiviral potential of APOBEC3 activity during HCMV infection, as well as the viral counteracting mechanisms under A3G-mediated selective pressure.

Original languageEnglish
Article numbere01224-18
Number of pages15
JournalJournal of Virology
Volume92
Issue number19
DOIs
Publication statusPublished - Oct 1 2018

Keywords

  • APOBEC3
  • gene editing
  • human cytomegalovirus
  • immune evasion

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Pautasso, S., Galitska, G., Dell'Oste, V., Biolatti, M., Cagliani, R., Forni, D., De Andrea, M., Gariglio, M., Sironi, M., & Landolfo, S. (2018). Strategy of Human Cytomegalovirus To Escape Interferon Beta-Induced APOBEC3G Editing Activity. Journal of Virology, 92(19), [e01224-18]. https://doi.org/10.1128/JVI.01224-18