Expression of E8∧E2 is required for wart formation by mouse papillomavirus 1 in vivo

Frank Stubenrauch, Elke Straub, Katrin Klein, Daniela Kramer, Thomas Iftner, Margaret Wong, Richard B.S. Roden

Research output: Contribution to journalArticlepeer-review

Abstract

Human papillomavirus (HPV) E1 and E2 proteins activate genome replication. E2 also modulates viral gene expression and is involved in the segregation of viral genomes. In addition to full-length E2, almost all papillomaviruses (PV) share the ability to encode an E8∧E2 protein, which is a fusion of E8 with the C-terminal half of E2 that mediates specific DNA binding and dimerization. HPV E8∧E2 acts as a repressor of viral gene expression and genome replication. To analyze the function of E8∧E2 in vivo, we used the Mus musculus PV1 (MmuPV1) mouse model system. Characterization of the MmuPV1 E8∧E2 protein revealed that it inhibits transcription from viral promoters in the absence and presence of E1 and E2 proteins and that this is partially dependent upon the E8 domain. MmuPV1 genomes in which the E8 ATG start codon was disrupted (E8-) displayed a 10- to 25-fold increase in viral gene expression compared to that of wild-type (wt) genomes in cultured normal mouse tail keratinocytes in short-term experiments. This suggests that the function and mechanism of E8∧E2 is conserved between MmuPV1 and HPV. Surprisingly, challenge of athymic nude Foxn1nu/nu mice with MmuPV1 E8- genomes did not induce warts on the tail, in contrast to wt MmuPV1. Furthermore, viral gene expression was completely absent at E8- MmuPV1 sites 20 to 22 weeks after DNA challenge on the tail or quasivirion (QV) challenge in the vaginal vault. This reveals that expression of E8∧E2 is necessary to form tumors in vivo and that this is independent from the presence of T cells.

Original languageEnglish (US)
Article numbere01930
JournalJournal of virology
Volume95
Issue number8
DOIs
StatePublished - Apr 2021

Keywords

  • E8∧E2
  • MmuPV1
  • Papillomavirus
  • Transcription repressor

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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