Human papillomavirus type 31 oncoproteins E6 and E7 are required for the maintenance of episomes during the viral life cycle in normal human keratinocytes

  • Jennifer T. Thomas
    Department of Microbiology—Immunology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611
  • Walter G. Hubert
    Department of Microbiology—Immunology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611
  • Margaret N. Ruesch
    Department of Microbiology—Immunology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611
  • Laimonis A. Laimins
    Department of Microbiology—Immunology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611

説明

<jats:p> The E6 and E7 oncoproteins of the high-risk human papillomavirus (HPV) types are able to immortalize human keratinocytes <jats:italic>in vitro</jats:italic> and likely contribute to the development of anogenital malignancies <jats:italic>in vivo</jats:italic> . The role of these oncoproteins in the productive viral life cycle, however, is not known. To begin to examine these possible roles, mutations in E6 were introduced in the context of the complete HPV 31 genome. Although transfected wild-type HPV 31 genomes, as well as genomes containing an E6 translation termination linker, an E6 frameshift mutation, and a point mutation in the p53 interacting domain were able to replicate in transient assays, only the wild-type genome was stably maintained as an episome. Interestingly, mutant genomes in either the E6 splice-donor site or splice-acceptor site were reduced in replication ability in transient assays; however, cotransfection of E1 and E2 expression vectors restored this function. In a similar fashion, genomes containing mutant HPV 31 E7 genes, including a translation termination mutant, two Rb-binding site mutants, a casein kinase II phosphorylation site mutant, and a transformation deficient mutant, were constructed. Although transient replication was similar to wild type in all of the E7 mutants, only the casein kinase II mutant had the ability to maintain high copies of episomal genomes. These findings suggest a role for E6 and E7 in the viral life cycle beyond their ability to extend the life span of infected cells. </jats:p>

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