Enhanced expression of the HPV 16 E6-E7 oncogenes may trigger neoplastic transformation of the squamous epithelial cells at the uterine cervix. The HPV E2 protein is a key transcriptional regulator of the E6-E7 genes. It binds to four E2 binding sites (E2BSs 1-4) in the viral upstream regulatory region (URR). Modification of E2 functions, for example, by methylation of E2BSs is hypothesized to trigger enhanced expression of the viral E6-E7 oncogenes. In the majority of HPV-transformed premalignant lesions and about half of cervical carcinomas HPV genomes persist in an extra-chromosomal, episomal state, whereas they are integrated into host cells chromosomes in the remaining lesions. Here we compared the methylation profile of E2BSs 1-4 of the HPV 16 URR in a series of 18 HPV16-positive premalignant lesions and 33 invasive cervical cancers. CpGs within the E2BSs 1, 3, and 4 were higher methylated in all lesions with only episomal HPV16 genomes compared with lesions displaying single integrated copies. Samples with multiple HPV16 integrated copies displayed high methylation levels for all CpGs suggesting that the majority of multiple copies were silenced by extensive methylation. These data support the hypothesis that differential methylation of the E2BSs 1, 3 and 4 is related to the activation of viral oncogene expression in cervical lesions as long as the viral genome remains in the episomal state. Once the virus becomes integrated into host cell chromosomes these methylation patterns may be substantially altered due to complex epigenetic changes of integrated HPV genomes.Persistent infections with high-risk human papillomaviruses (HR-HPVs) are the primary cause of cancer at various sites of the anogenital tract, including the cervix, vulva, vagina, penis and anus, as well as a subset of head and neck cancers. 1 The predominant HR-HPV type in cervical cancers is HPV16, accounting alone for about 50% of all cervical cancers. 2 It is commonly accepted that HPVs infect the basal cells of the squamous epithelium. Oncogenic human papillomaviruses encode two well-characterized oncoproteins, E6 and E7 that are under tight transcriptional control in early permissive, but not yet transformed genital HPV-infections. The enhanced expression of these oncogenes in basal and parabasal squamous epithelial cells of the infected epithelium is the cause of neoplastic transformation of the infected cells. 3,4 The main transforming properties of the E6 and E7 oncoproteins are related to their ability to inactivate the p53 and retinoblastoma (pRB) tumor suppressor proteins, respectively. 4-7 E7 overexpression in HPV-infected cells is accompanied by substantial overexpression of the cyclin-dependent kinase inhibitor p16 INK4a . p16 INK4a overexpression is therefore used as surrogate biomarker for HPV-transformed epithelial cells. 8 Expression of the E6 and E7 genes is regulated by the upstream regulatory region (URR). The HPV 16 URR contains sequences that regulate transcription and replication of the viral genome to which both cell...

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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.

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Background Dengue, a viral disease transmitted by Aedes mosquitoes, is an important public health concern throughout Thailand. Climate variables are potential predictors of dengue transmission. Associations between climate variables and dengue have usually been performed on large-scale first-level national administrative divisions, i.e. provinces. Here we analyze data on a finer spatial resolution in one province, which is often more relevant for effective disease control design. The objective of this study was to investigate the effect of seasonal variations, monthly climate variability, and to identify local clusters of symptomatic disease at the sub-district level based on reported dengue cases. Methods Data on dengue cases were retrieved from the national communicable disease surveillance system in Thailand. Between 2006 and 2016, 15,167 cases were recorded in 199 sub-districts of Khon Kaen Province, northeastern Thailand. Descriptive analyses included demographic characteristics and temporal patterns of disease and climate variables. The association between monthly disease incidence and climate variations was analyzed at the sub-district level using Bayesian Poisson spatial regression. A hotspot analysis was used to assess the spatial patterns (clustered/dispersed/random) of dengue incidence. Results Dengue was predominant in the 5–14 year-old age group (51.1%). However, over time, dengue incidence in the older age groups (> 15 years) gradually increased and was the most affected group in 2013. Dengue outbreaks coincide with the rainy season. In the spatial regression model, maximum temperature was associated with higher incidence. The hotspot analysis showed clustering of cases around the urbanized area of Khon Kaen city and in rural areas in the southwestern portion of the province. Conclusions There was an increase in the number of reported dengue cases in older age groups over the study period. Dengue incidence was highly seasonal and positively associated with maximum ambient temperature. However, climatic variables did not explain all the spatial variation of dengue in the province. Further analyses are needed to clarify the detailed effects of urbanization and other potential environmental risk factors. These results provide useful information for ongoing prediction modeling and developing of dengue early warning systems to guide vector control operations. Electronic supplementary material The online version of this article (10.1186/s12879-019-4379-3) contains supplementary material, which is available to authorized users.