In vitro synthesis of oncogenic human papillomaviruses requires episomal genomes for differentiation-dependent late expression - PubMed (original) (raw)
In vitro synthesis of oncogenic human papillomaviruses requires episomal genomes for differentiation-dependent late expression
M G Frattini et al. Proc Natl Acad Sci U S A. 1996.
Abstract
Human papillomavirus (HPV) types 16, 18, 31, and 51 are the etiologic agents of many anogenital cancers including those of the cervix. These "high risk" HPVs specifically target genital squamous epithelia, and their lytic life cycle is closely linked to epithelial differentiation. We have developed a genetic assay for HPV functions during pathogenesis using recircularized cloned HPV 31 genomes that were transfected together with a drug resistance marker into monolayer cultures of normal human foreskin keratinocytes, the natural host cell. After drug selection, cell lines were isolated that stably maintained HPV 31 DNA as episomes and underwent terminal differentiation when grown in organotypic raft cultures. In differentiated rafts, the expression of late viral genes, amplification of viral DNA, and production of viral particles were detected in suprabasal cells. This demonstrated the ability to synthesize HPV 31 virions from transfected DNA templates and allowed an examination of HPV functions during the vegetative viral life cycle. We then used this system to investigate whether an episomal genome was required for the induction of late viral gene expression. When an HPV 31 genome (31E1*) containing a missense mutation in the E1 open reading frame was transfected into normal human keratinocytes, the mutant viral sequences were found to integrate into the host cell chromosomal DNA with both early and late regions intact. While high levels of early viral gene transcription were observed, no late gene expression was detected in rafts of cell lines containing the mutant viral genome despite evidence of terminal differentiation. Therefore, the induction of late viral gene expression required that the viral genomes be maintained as extrachromosomal elements, and terminal differentiation alone was not sufficient. These studies provide the basis for a detailed examination of HPV functions during viral pathogenesis.
Similar articles
- Induction of human papillomavirus type 18 late gene expression and genomic amplification in organotypic cultures from transfected DNA templates.
Frattini MG, Lim HB, Doorbar J, Laimins LA. Frattini MG, et al. J Virol. 1997 Sep;71(9):7068-72. doi: 10.1128/JVI.71.9.7068-7072.1997. J Virol. 1997. PMID: 9261437 Free PMC article. - Role of the E1--E4 protein in the differentiation-dependent life cycle of human papillomavirus type 31.
Wilson R, Fehrmann F, Laimins LA. Wilson R, et al. J Virol. 2005 Jun;79(11):6732-40. doi: 10.1128/JVI.79.11.6732-6740.2005. J Virol. 2005. PMID: 15890911 Free PMC article. - Human papillomavirus type 31 E5 protein supports cell cycle progression and activates late viral functions upon epithelial differentiation.
Fehrmann F, Klumpp DJ, Laimins LA. Fehrmann F, et al. J Virol. 2003 Mar;77(5):2819-31. doi: 10.1128/jvi.77.5.2819-2831.2003. J Virol. 2003. PMID: 12584305 Free PMC article. - Biology and pathological associations of the human papillomaviruses: a review.
Cheah PL, Looi LM. Cheah PL, et al. Malays J Pathol. 1998 Jun;20(1):1-10. Malays J Pathol. 1998. PMID: 10879257 Review. - Pathogenesis of human papillomaviruses in differentiating epithelia.
Longworth MS, Laimins LA. Longworth MS, et al. Microbiol Mol Biol Rev. 2004 Jun;68(2):362-72. doi: 10.1128/MMBR.68.2.362-372.2004. Microbiol Mol Biol Rev. 2004. PMID: 15187189 Free PMC article. Review.
Cited by
- Human papillomavirus molecular prevalence in south China and the impact on vaginal microbiome of unvaccinated women.
Wang T, Li W, Cai M, Ji S, Wang Y, Huang N, Jiang Y, Zhang Z. Wang T, et al. mSystems. 2024 Sep 17;9(9):e0073824. doi: 10.1128/msystems.00738-24. Epub 2024 Aug 9. mSystems. 2024. PMID: 39120153 Free PMC article. - The immune microenvironment of cancer of the uterine cervix.
Mastrogeorgiou M, Chatzikalil E, Theocharis S, Papoudou-Bai A, Péoc'h M, Mobarki M, Karpathiou G. Mastrogeorgiou M, et al. Histol Histopathol. 2024 Oct;39(10):1245-1271. doi: 10.14670/HH-18-727. Epub 2024 Mar 1. Histol Histopathol. 2024. PMID: 38483012 Review. - Effect of HPV Oncoprotein on Carbohydrate and Lipid Metabolism in Tumor Cells.
Chen B, Wang Y, Wu Y, Xu T. Chen B, et al. Curr Cancer Drug Targets. 2024;24(10):987-1004. doi: 10.2174/0115680096266981231215111109. Curr Cancer Drug Targets. 2024. PMID: 38284713 Review. - Characterization of 3D organotypic epithelial tissues reveals tonsil-specific differences in tonic interferon signaling.
Jackson R, Rajadhyaksha EV, Loeffler RS, Flores CE, Van Doorslaer K. Jackson R, et al. PLoS One. 2023 Oct 4;18(10):e0292368. doi: 10.1371/journal.pone.0292368. eCollection 2023. PLoS One. 2023. PMID: 37792852 Free PMC article. - p53-dependent R-loop formation and HPV pathogenesis.
Templeton CW, Laimins LA. Templeton CW, et al. Proc Natl Acad Sci U S A. 2023 Aug 29;120(35):e2305907120. doi: 10.1073/pnas.2305907120. Epub 2023 Aug 23. Proc Natl Acad Sci U S A. 2023. PMID: 37611058 Free PMC article.
References
- J Biol Chem. 1978 Aug 25;253(16):5861-8 - PubMed
- J Virol. 1995 Jun;69(6):3381-8 - PubMed
- Mol Cell Biol. 1985 Jun;5(6):1391-9 - PubMed
- Virology. 1989 Jul;171(1):306-11 - PubMed
- J Virol. 1990 Oct;64(10):5093-105 - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources