Abstract
In the early stages of human papillomavirus (HPV) infection, the viral proteins elicit specific immune responses that can participate to regression of ano-genital lesions. HPV E6 protein for instance can reduce type I interferon (IFN) including IFN-κ that is involved in immune evasion and HPV persistence. To evaluate the role of E2 protein in innate immunity in HPV16-associated cervical lesions, genome-wide expression profiling of human primary keratinocytes (HPK) transduced by HPV16 E2 was investigated using microarrays and innate immunity associated genes were specifically analyzed. The analyses showed that the expression of 779 genes was modulated by HPV16E2 and 92 of them were genes associated with innate immunity. Notably IFN-κ and STING were suppressed in HPK expressing the E2 proteins of HPV16 or HPV18 and the trans-activation amino-terminal domain of E2 was involved in the suppressive effect. The relationship between STING, IFN-κ and interferon stimulated genes (ISGs) in HPK was confirmed by gene silencing and real time PCR. The expression of STING and IFN-κ were further determined in clinical specimens by real time PCR. STING and IFN-κ were down-modulated in HPV positive low grade squamous intraepithelial lesions compared with HPV negative controls. This study demonstrates that E2 proteins of high risk HPV reduce STING and IFN-κ transcription and its downstream target genes that might be an immune evasion mechanism involved in HPV persistence and cervical cancer development.
Highlights
Human papillomavirus (HPV) infection is the most common sexually transmitted infection with approximately 50–80% of sexually active adults acquiring one or more HPV types during their lifetime
Partial cytoplasmic localization of the GFP fusion proteins was found in the cells transduced with GFPHPV16E2, GFP-HPV18E2, and GFP-HPV18E2TAD whereas the GFP-HPV18E2DBD was mostly found in nucleus
stimulator of interferon genes (STING) interacts with TANKbinding kinase 1 (TBK1) and interferon response factors (IRF)-3 leading to the phosphorylation of IRF-3 and production of type I IFN [40]
Summary
Human papillomavirus (HPV) infection is the most common sexually transmitted infection with approximately 50–80% of sexually active adults acquiring one or more HPV types during their lifetime. The risk of infection is depending on numerous factors including host factors such as the number of sexual partners, age of sexual activity and genetic background as well as viral factors such as the specific viral genotype [1,2]. HPV genotypes infecting the ano-genital mucosal epithelium are categorized as ‘low-risk’ (LR-HPV) or ‘high-risk’ types (HRHPV), depending on their association with either benign lesions or lesions that can progress to cancers [3]. Approximately 10–20% of infected women have persisting HR-HPV infection and progress to high grade cervical intra-epithelial neoplasia, CIN2/3 and invasive cancer [8]. Lack of effective immune responses is a potent factor to carcinogenic progression
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
