Human papillomavirus (HPV) 11/16 E6/E7 proteins have been recognized to be pivotal in viral pathogenesis. This study sought to uncover the potential mechanisms of how HPV11/16 E6/E7-transfected keratinocytes inhibit cytokine secretion in peripheral blood mononuclear cells (PBMC). Upon co-culturing HPV11/16 E6/E7-transfected keratinocytes with PBMC in a non-contact manner, we observed a marked decrease in various cytokines secreted by PBMC. To determine if this suppression was mediated by specific common secreted factors, we conducted transcriptomic sequencing on these transfected cells. This analysis identified 53 common differentially secreted genes in all four HPV-transfected cells. Bioinformatics analysis demonstrated these genes were predominantly involved in immune regulation. Results from quantitative PCR (qPCR) and an extensive literature review suggested the downregulation of 12 genes (ACE2, BMP3, BPIFB1, CLU, CST6, CTF1, HMGB2, MMP12, PDGFA, RNASE7, SULF2, TGM2), and upregulation of 7 genes (CCL17, CCL22, FBLN1, PLAU, S100A7, S100A8, S100A9), may be crucial in modulating tumor immunity and combating pathogenic infections, with genes S100A8 and S100A9, and IL-17 signaling pathway being particularly noteworthy. Thus, HPV11/16 E6/E7 proteins may inhibit cytokine secretion of immune cells by altering the expression of host-secreted genes. Further exploration of these genes may yield new insights into the complex dynamics of HPV infection.

Juvenile onset recurrent respiratory papillomatosis is a lifelong benign squamous lesion associated with HPV infection, particularly HPV6 and HPV11 genotypes. These lesions are rare, but can lead to laryngeal obturations, which can cause disabling dyspnea, or transform into squamous cell carcinoma. The aim here is to provide an epidemiological, biological and clinical overview of this pathology, particularly in children, in order to understand the issues at stake in terms of research and the development of medical and therapeutic management tools.

Recurrent respiratory papillomatosis (RRP) is a rare benign tumor caused mainly by the infection of the respiratory tract epithelial cells by the human papillomavirus (HPV) type 6/11. However, the specific mechanisms underlying the inhibition of the host\'s innate immune response by HPV remain unclear. For this purpose, we employed single-cell RNA sequencing to analyze the states of various immune cells in RRP samples post-HPV infection and utilized a cellular model of HPV infection to elucidate the mechanisms by which HPV evades the innate immune system in RRP. The results revealed distinct immune cell heterogeneity in RRP and demonstrated that HPV11 E7 can inhibit the phosphorylation of the stimulator of interferon genes protein, thereby circumventing the body\'s antiviral response. In vitro co-culture experiments demonstrated that stimulation of macrophages to produce interferon-beta induced the death of HPV-infected epithelial cells, also reducing HPV viral levels. In summary, our study preliminarily identifies the potential mechanisms by which HPV evades the host\'s antiviral immune response, as well as the latent antiviral functions exhibited by activated macrophages. This research serves as an initial exploration of antiviral immune evasion in RRP, laying a solid foundation for investigating immunotherapeutic approaches for the disease.IMPORTANCESurgical tumor reduction is the most common treatment for recurrent respiratory papillomatosis (RRP). One of the characteristics of RRP is its persistent recurrence, and multiple surgeries are usually required to control the symptoms. Recently, some adjuvant therapies have shown effectiveness, but none of them can completely clear human papillomavirus (HPV) infection, and thus, a localized antiviral immune response is significant for disease control; after all, HPV infection is limited to the epithelium. Inhibition of interferon-beta (IFN-β) secretion by HPV11 E7 viral proteins in epithelial cells by affecting stimulator of interferon genes phosphorylation may account for the persistence of low-risk HPV replication in the RRP. Moreover, suppression of the IFN-I pathway in RRP cell types might provide clues regarding the hyporeactive function of local immune cells. However, activation of macrophage groups to produce IFN-β can still destroy HPV-infected cells.

暂无摘要。

Laryngeal human papillomavirus (HPV) infection causes recurrent respiratory papillomatosis (RRP) and accounts for up to 25% of laryngeal cancers. Lack of satisfactory preclinical models is one reason that treatments for these diseases are limited. We sought to assess the literature describing preclinical models of laryngeal papillomavirus infection.
PubMed, Web of Science, and Scopus were searched from the inception of database through October 2022.
Studies searched were screened by two investigators. Eligible studies were peer-reviewed, published in English, presented original data, and described attempted models of laryngeal papillomavirus infection. Data examined included type of papillomavirus, infection model, and results including success rate, disease phenotype, and viral retention.
After screening 440 citations and 138 full-text studies, 77 studies published between 1923 and 2022 were included. Models used low-risk HPV or RRP (n = 51 studies), high-risk HPV or laryngeal cancer (n = 16), both low- and high-risk HPV (n = 1), and animal papillomaviruses (n = 9). For RRP, 2D and 3D cell culture models and xenografts retained disease phenotypes and HPV DNA in the short term. Two laryngeal cancer cell lines were consistently HPV-positive in multiple studies. Animal laryngeal infections with animal papillomaviruses resulted in disease and long-term retention of viral DNA.
Laryngeal papillomavirus infection models have been researched for 100 years and primarily involve low-risk HPV. Most models lose viral DNA after a short duration. Future work is needed to model persistent and recurrent diseases, consistent with RRP and HPV-positive laryngeal cancer.
NA Laryngoscope, 133:3256-3268, 2023.

UNASSIGNED: The aim of this study was to describe the clinical presentation and outcome of patients with adult-onset recurrent respiratory papillomatosis (AoRRP) in a developing country with the challenges of poor health care access and high prevalence of HIV infection.
UNASSIGNED: This was a retrospective study of patients diagnosed with AoRRP who were managed in the Department of Otorhinolaryngology at Universitas Academic Hospital in Bloemfontein, South Africa over a 10 year period.
UNASSIGNED: There were a total of 41 patients, of which 26 (63.4%) were male. The age at diagnosis ranged between 16.4 and 67.4 years (mean 39.4 ± 14.9 years). All patients presented with a hoarse voice, with three patients also having upper airway obstruction. Eight (19.5%) patients were HIV positive. HPV typing was performed in 29 patients; 14 had HPV11 disease, 12 had HPV6 disease and in 3 patients HPV DNA was not detected. There was no significant difference in initial presentation or outcome between HIV negative and HIV positive patients, or between patients with HPV6 and HPV11 disease. Two patients had malignant transformation of the papillomas. In both these patients, HPV was not detected in the papillomas.
UNASSIGNED: HPV type and HIV infection did not appear to influence the clinical presentation and outcome in patients with AoRRP. There is a risk of malignant transformation in patients in which HPV is not detected in the papillomas.

The human papillomavirus (HPV) vaccine is effective at reducing the incidence of cervical cancer caused by HPV. Studies have shown that 1 dose of the HPV vaccine offers comparable protection against genital HPV infection as additional doses; however, it is unknown whether oral HPV prevalence also differs by number of vaccine doses. We examined differences in prevalence of oral HPV by number of doses using the National Health and Nutrition Examination Survey from 2009 to 2016. The prevalence of HPV 6, 11, 16, and 18 infections was statistically significantly lower in individuals who received 1 dose (0.3%, 95% confidence interval [CI] = 0.0% to 0.9%) or 2-3 doses (0.4%, 95% CI = 0.0% to 1.2%) compared with unvaccinated individuals (1.2%, 95% CI = 0.9% to 1.6%). Smokers, individuals who initiated oral sex at age 17 years or younger, and those with more than 2 oral sexual partners had higher rates of oral HPV infection. Ongoing prospective studies are essential to further evaluate the efficacy of a single-dose regimen for prevention of oral HPV.

Laryngeal papilloma (LP), which is associated with infection by human papillomavirus (HPV)-6 or -11, displays aggressive growth. The precise molecular mechanism underlying the tumorigenesis of LP has yet to be uncovered. Building on our earlier research into HPV-6, in this study, the viral gene expression of HPV-11 was investigated by quantitative PCR and DNA/RNA in situ hybridization. Additionally, newly developed antibodies against the E4 protein of HPV-6 and HPV-11 were evaluated by immunohistochemistry. The average viral load of HPV-11 in LP was 1.95 ± 0.66 × 105 copies/ng DNA, and 88% of HPV mRNA expression was found to be E4, E5a, and E5b mRNAs. According to RNA in situ hybridization, E4 and E5b mRNAs were expressed from the middle to upper part of the epithelium. E4 immunohistochemistry revealed a wide positive reaction in the upper cell layer in line with E4 mRNA expression. Other head and neck lesions with HPV-11 infection also showed a positive reaction in E4 immunohistochemistry. The distribution pattern of HPV DNA, viral mRNA, and E4 protein in LP with HPV-11 infection was quite similar to that of HPV-6. Therefore, it might be possible to apply these E4-specific antibodies in other functional studies as well as clinical applications, including targeted molecular therapies in patients with HPV-6 and HPV-11 infection.

BACKGROUND: Juvenile-onset recurrent respiratory papillomatosis (JORRP) is a rare disease characterized by the growth of papillomas in the respiratory tract. In the United States, JORRP is not a nationally notifiable condition and current data are limited.
METHODS: Children with JORRP aged <18 years were enrolled from 26 pediatric otolaryngology centers in 23 US states from January 2015 through August 2020. Demographic, birth information, and maternal vaccination history were collected from a parent/guardian. Clinical history was abstracted from medical records. Papilloma biopsies were tested for 28 human papillomavirus (HPV) types. Mothers who delivered in 2006 or later were considered age-eligible for HPV vaccination if aged ≤26 years in 2006. We described characteristics of enrolled children and their birth mothers and analyzed disease severity by diagnosis age and HPV type using multiple logistic regression.
RESULTS: Among 215 children with JORRP, 88.8% were delivered vaginally; 64.2% were firstborn. Among 190 mothers, the median delivery age was 22 years. Among 114 (60.0%) age-eligible for HPV vaccination, 16 (14.0%) were vaccinated, 1 (0.9%) before delivery. Among 162 specimens tested, 157 (96.9%) had detectable HPV; all 157 had a vaccine-preventable type. Disease severity was associated with younger diagnosis age and HPV 11; adjusted analyses found only younger diagnosis age significant (adjusted odds ratio: 6.1; 95% confidence interval: 2.9, 12.8).
CONCLUSIONS: Children with JORRP were commonly firstborn and delivered vaginally to young mothers; most of the mothers reported no HPV vaccination before delivery. Vaccine-preventable HPV was identified in all specimens with detectable HPV. Increasing preexposure HPV vaccination could substantially reduce or eliminate JORRP in the United States.

BACKGROUND: Low-risk human papillomavirus (HPV), such as types 6 and 11, is considered non-oncogenic, but these types have been detected in oral cancer tissue samples, suggesting their possible involvement in oral carcinogenesis. Because double infection of high-risk HPV and Epstein-Barr virus (EBV) is known to be involved in oral carcinogenesis, we hypothesized that low-risk HPV and EBV co-infection can transform the oral cells. To verify our hypothesis, we evaluated the transformation activity of cell lines expressing both low-risk HPV E6/E7 and EBV LMP-1.
METHODS: We transduced HPV6, 11 and 16 E6/E7 genes and EBV LMP-1 gene into primary mouse embryonic fibroblasts. The cell lines were examined for indices of transformation activity such as proliferation, induction of DNA damage, resistance to apoptosis, anchorage-independent growth, and tumor formation in nude mice. To evaluate the signaling pathways involved in transformation, NF-κB and p53 activities were analyzed. We also assessed adhesion signaling molecules associated with anchorage-independent growth such as MMP-2, paxillin and Cat-1.
RESULTS: Co-expression of low-risk HPV6 E6 and EBV LMP-1 showed increased cell proliferation, elevated NF-κB activity and reduced p53 induction. Moreover, co-expression of low-risk HPV6 E6 and EBV LMP-1 induced DNA damage, escaped from apoptosis under genotoxic condition and suppression of DNA damage response (DDR). Co-expression of low-risk HPV11 E6/E7 and EBV LMP-1 demonstrated similar results. However, it led to no malignant characteristics such as anchorage-independent growth, invasiveness and tumor formation in nude mice. Compared with the cells co-expressing high-risk HPV16 E6 and EBV LMP-1 that induce transformation, co-expression of low-risk HPV6 E6 and EBV LMP-1 was associated with low MMP-2, paxillin and Cat-1 expression.
CONCLUSIONS: The co-expression of low-risk HPV E6/E7 and EBV LMP-1 does not induce malignant transformation, but it allows accumulation of somatic mutations secondary to increased DNA damage and suppression of DDR. Thus, double infection of low-risk HPV and EBV could lead to precancerous lesions.