Interferon-beta treatment increases human papillomavirus early gene transcription and viral plasmid genome replication by activating interferon regulatory factor (IRF)-1.
Interferons (IFNs) have been used to treat mucosal lesions caused by human papillomavirus (HPV) infection, such as intraepithelial precursor lesions to cancer of the uterine cervix, genital warts or recurrent respiratory papillomatosis, to potentially reduce or eliminate replicating HPV plasmid genomes. Mucosal HPVs have evolved mechanisms that impede IFN-beta synthesis and downregulate genes induced by IFN. Here we show that these HPV types directly subvert a cellular transcriptional response to IFN-beta as a potential boost in infection. Treatment with low levels of human IFN-beta induced initial amplification of HPV-16 and HPV-11 plasmid genomes and increased HPV-16 or HPV-31 DNA copy numbers up to 6-fold in HPV-immortalized keratinocytes. IFN treatment also increased early gene transcription from the major early gene promoters in HPV-16, HPV-31 and HPV-11. Furthermore, mutagenesis of the viral genomes and ectopic interferon regulatory factor (IRF) expression in transfection experiments using IRF-1(-/-), IRF-2(-/-) and dual knockout cell lines determined that these responses are due to the activation of IRF-1 interaction with a conserved interferon response element demonstrated in several mucosal HPV early gene promoters. Our results provide a molecular explanation for the varying clinical outcomes of IFN therapy of papillomatoses and define an assay for the modulation of the HPV gene program by IFNs as well as other cytokines and signaling molecules in infection and therapy.
Lace
Michael J
MJ
Veterans Affairs Medical Center, Iowa City, IA 52246, USA. michael-lace@uiowa.edu
Anson
James R
JR
Klingelhutz
Aloysius J
AJ
Harada
Hisashi
H
Taniguchi
Tadatsugu
T
Bossler
Aaron D
AD
Haugen
Thomas H
TH
Turek
Lubomir P
LP
D000818:Animals; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000737:chemistry; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D015967:Gene Expression Regulation, Viral; D016679:Genome, Viral; D052140:Human papillomavirus 11 / Q000235:genetics*; D052162:Human papillomavirus 16 / Q000235:genetics*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D050836:Interferon Regulatory Factor-2 / Q000502:physiology; D016899:Interferon-beta / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000235:genetics; D020218:Response Elements; D014158:Transcription, Genetic / Q000187:drug effects; D014779:Virus Replication
D017931:DNA Primers; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; C494258:Irf1 protein, mouse; C494230:Irf2 protein, mouse; D016899:Interferon-beta