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.

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The genome of human papillomaviruses (HPVs) encodes the E1 replication factor, whose biological activities are regulated by cellular protein kinases. Here, the phosphorylation pattern of the E1 helicase of oncogenic mucosotropic HPV18 was investigated both in vitro and in vivo. Four serine residues located in a short peptide within a localization regulatory region were found to be phosphorylated in both experimental settings. We demonstrate that this peptide is targeted in vitro by various protein kinases, including CK2, PKA, and CKD2/cyclin A/B/E complexes. Through point mutagenesis, we show that phosphorylation of this region is essential for E1 subcellular localization, the interaction of E1 with the E2 protein, and replication of the HPV18 genome. Furthermore, we demonstrate the functional conservation of this phosphorylation across the E1 proteins of the low-risk mucosotropic HPV11 and high-risk cutaneotropic HPV5. These findings provide deeper insights into the phosphorylation-mediated regulation of biological activities of the E1 protein.

UNASSIGNED: This study aims to understand the clinical characteristics of male HPV infection and provide data and information for the prevention and health of the male and female reproductive tracts in the region.
UNASSIGNED: A total of 390 male patients who underwent HPV examinations in outpatient clinics and physical examinations in 363 hospitals from December 2017 to May 2022 were selected. Samples were collected, and HPV genotyping was performed using multiplex fluorescent PCR. The HPV infection rate, genotype distribution, age distribution, and clinical symptom distribution were analyzed.
UNASSIGNED: Out of 3,816 samples, the total HPV infection rate was 47.44% (185/390). The HPV infection rate in the symptomatic group was 57.09% (141/247), significantly higher than that in the asymptomatic group (P < .01). Among the subtypes, HPV6 accounted for the highest proportion (31.03%, 90/290), followed by HPV11 (14.14%, 41/290) and HPV52 (8.62%, 25/290). Types 6 and 11 were mainly concentrated in the symptomatic group (91.11%, 85.37%). The highest positive rate was observed in the 17-30-year-old group (45.41%, 85/185), followed by the 31-40-year-old group (28.11%, 52/185). The proportion of HPV infections with clinical symptoms of abnormal growth was 84.40% (119/141). HPV6 or/and HPV11 infections were mainly concentrated in the abnormal growth group, accounting for 90.76% (108/113).
UNASSIGNED: The rates of male HPV infection are high, particularly among individuals aged 17-40. Low-risk infections (types 6 and 11) cause male reproductive tract symptoms, including abnormal growth. High-risk infection (HPV52) correlates with local women\'s HPV subtype distribution and potential transmission. Therefore, screening for male HPV infection is crucial in preventing cervical cancer. Authorities should promote the development and early use of male HPV vaccines.

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.

To evaluate the safety, immunogenicity, and efficacy of INO-3107, a DNA immunotherapy designed to elicit targeted T-cell responses against human papillomavirus (HPV) types 6 and 11, in adult patients with recurrent respiratory papillomatosis (RRP; NCT04398433).
Eligible patients required ≥2 surgical interventions for RRP in the year preceding dosing. INO-3107 was administered by intramuscular (IM) injection followed by electroporation (EP) on weeks 0, 3, 6, and 9. Patients underwent surgical debulking within 14 days prior to first dose, with office laryngoscopy and staging at screening and weeks 6, 11, 26, and 52. Primary endpoint was safety and tolerability, as assessed by treatment-emergent adverse events (TEAEs). Secondary endpoints included frequency of surgical interventions post-INO-3107 and cellular immune responses.
An initial cohort of 21 patients was enrolled between October 2020 and August 2021. Fifteen (71.4%) patients had ≥1 TEAE; 11 (52.4%) were Grade 1, and 3 (14.3%) were Grade 3 (none treatment related). The most frequently reported TEAE was injection site or procedural pain (n = 8; 38.1%). Sixteen (76.2%) patients had fewer surgical interventions in the year following INO-3107 administration, with a median decrease of 3 interventions versus the preceding year. The RRP severity score, modified by Pransky, showed improvement from baseline to week 52. INO-3107 induced durable cellular responses against HPV-6 and HPV-11, with an increase in activated CD4 and CD8 T cells and CD8 cells with lytic potential.
The data suggest that INO-3107 administered by IM/EP is tolerable and immunogenic and provides clinical benefit to adults with RRP.
3 Laryngoscope, 133:3087-3093, 2023.

Recurrent respiratory papillomatosis (RRP) has a wide range of severity. We investigate the relationship between human papillomavirus (HPV) particle production and severity of RRP. From September 2005 to June 2021, 68 RRP samples (from 29 patients) were included. HPV type was determined. HPV viral load, physical status, and demographic and clinical characteristics were assessed. Immunohistochemistry (IHC) was performed for p16, Ki-67, L1, and E4. We used NanoSuit-CLEM (correlative light and electron microscopy) and transmission electron microscopy (TEM) to examine the samples. The total number of surgeries in HPV-positive and HPV-negative cases were 3.78 (n = 55/68, range: 1-16) and 1.30 (n = 13/68, range: 1-3), respectively (p = 0.02). IHC showed that L1 and E4 were correlated and expressed on the tumour surface. NanoSuit-CLEM and TEM revealed HPV particles in L1-positive nuclei. L1 IHC-positive cases had a shorter surgical interval (p < 0.01) and more frequent surgeries (p = 0.04). P16 IHC, viral load, and physical status were not associated with disease severity. This study visualised HPV particle production in RRP for the first time. Persistent HPV particle infection was associated with severity. We suggest L1 IHC for evaluating RRP severity in addition to the Derkay score.

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.