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.

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.

Laryngopharynx epithelium neoplasia induced by HPV6/11 infection in juvenile-onset recurrent respiratory papillomatosis (JO-RRP) causes a great health issue characteristic of frequent relapse and aggressive disease progression. Local cell-mediated immunity shaped by the recruitment and activation of cytotoxic effector cells is critical for viral clearance. In this study, we found that NK cells in the papillomas of aggressive JO-RRP patients, in contrast to massive infiltrated T cells, were scarce in number and impaired in activation and cytotoxicity as they were in peripheral blood. Data from cell infiltration analysis indicated that the migration of NK cell to papilloma was restricted in aggressive JO-RRP patients. Further study showed that the skewed chemokine expression in the papillomas and elevated ICAM-1 expression in hyperplastic epithelia cells favored the T cell but not NK cell recruitment in aggressive JO-RRP patients. In parallel to the increased CD3+ T cells, we observed a dramatical increase in Tregs and Treg-promoting cytokines such as IL-4, IL-10 and TGFβ in papillomas of aggressive JO-RRP patients. Our study suggested that likely initialized by the intrinsic change in neoplastic epithelial cells with persistent HPV infection, the aggressive papillomas built an entry barrier for NK cell infiltration and formed an immunosuppressive clump to fend off the immune attack from intra-papillomas NK cells. IMPORTANCE Frequent relapse and aggressive disease progression of juvenile-onset recurrent respiratory papillomatosis (JO-RRP) pose a great challenge to the complete remission of HPV 6/11 related laryngeal neoplasia. Local immune responses in papillomas are more relevant to the disease control considering the locale infected restriction of HPV virus in epitheliums. In our study, the restricted NK cell number and reduced expression of activating NKp30 receptor suggested one possible mechanism underlying impaired NK cell defense ability in aggressive JO-RRP papillomas. Meanwhile, the negative impact of HPV persistent infection on NK cell number and function represented yet another example of a chronic pathogen subverting NK cell behavior, affirming a potentially important role for NK cells in viral containment. Further, the skewed chemokine/cytokine expression in the papillomas and the elevated adhesion molecules expression in hyperplastic epithelia cells provided important clues for understanding blocked infiltration and antiviral dysfunction of NK cells in papilloma.

Addressing the burden of HPV-associated diseases among men is increasingly becoming a public health issue. The main objective of this study was to determine HPV prevalence among a healthy community-based Malaysian men.
This was a cross-sectional study that recruited 503 healthy males from 3 community-based clinics in Selangor, Malaysia. Genital and anal samples were collected from each participant for 14 high risk and 2 low risk HPV DNA detection and genotyping. All participants responded to a set of detailed sociodemographic and sexual behaviour questionnaire.
The median age at enrolment was 40 years old (IQR: 31-50). The anogenital HPV6/11 prevalence was 3.2% whereas high risk HPV prevalence was 27.1%. The genital HPV prevalence for HPV6/11 was 2.9% while high risk HPV was 18.8%. HPV6/11 prevalence in the anal canal was 1.6% and high risk HPV was 12.7%. HPV 18 was the most prevalent genotype detected in the anogenital area. There was a significant independent association between genital and anal HPV infections.
Anogenital HPV infection is common among Malaysian men. These findings emphasize the ubiquity of HPV infection and thus the value of population-wide access to HPV prevention.

Human papillomavirus type 11 (HPV11) is one of the main causes of condyloma acuminatum, a widespread sexually transmitted disease. During infection of its primary target cell, keratinocytes, it is likely to encounter the autophagy pathway, which is an intracellular maintenance process that is also able to target invading pathogens. It is currently unknown whether HPV11 is targeted by autophagy or whether it is able to escape autophagy-mediated killing. Here, we investigated the autophagy response during HPV11 pseudovirion (PsV) entry in human keratinocytes. Transmission electron microscopy showed that intracellular PsVs were sequestered in lumen of double-membrane autophagosomes that subsequently appeared to fuse with lysosomes, while confocal microscopy showed induction LC3 puncta, the hallmark of induced autophagy activity. Furthermore, quantitative infection assays showed that high autophagy activity resulted in reduced HPV11 PsV infectivity. Therefore, the autophagy pathway seemed to actively target invading HPV11 PsVs for destruction in the autolysosome. Western analysis on the phosphorylation state of autophagy regulators and upstream pathways indicated that autophagy was activated through interplay between Erk and Akt signaling. In conclusion, autophagy functions as a cellular protection mechanism against intracellular HPV11 and therefore therapies that stimulate autophagy may prevent recurrent condyloma acuminatum by helping eliminate latent HPV11 infections.

Imiquimod (IMQ) is approved as a first-line treatment for genital warts caused by human papillomavirus (HPV) infection. However, the recurrence rate is very high. HPV E7 protein plays a critical role in HPV immune escape. However, the role of HPV11 E7 protein in genital warts recurrence during IMQ treatment is not clear. Here, we found that the expression profile of NHEK cells was obviously changed after IMQ treatment, and a large number of genes encoding cytokines and genes involved in cytokine-mediated signaling pathways and cellular metabolic signaling pathways were up- or downregulated. HPV11E7 overexpression inhibited the IMQ-induced production of of multiple chemokines and colony-stimulating factors in NHEK cells. Furthermore, we found that HPV11E7 could impair the activation of mitogen-activated protein kinase (MAPK) signaling pathway. Therefore, our results suggested that HPV11 E7 diminishes the production of chemokines, colony-stimulating factors and other cytokines via inhibition of the MAPK signaling pathway, which suppresses the therapeutic effect of IMQ and promotes the recurrence of diseases, such as condyloma acuminatum.

Representing the first line of host defense against virus infections and an essential link between innate and adaptive immune response, the role of dendritic cells (DCs) in peripheral blood of juvenile-onset recurrent respiratory papillomatosis (JORRP) patients and association with disease activity were still not established.
In our present study, 28 JORRP patients and 28 age and sex matched healthy controls were enrolled. The percentage, phenotype and cytokine secretion of DC and was measured by flow cytometry. Plasma cytokine were detected by the enzyme-linked immunosorbent assay (ELISA).
We found that the percentage of myeloid DC (mDC) was significantly lower in JORRP patients compared to healthy controls and was negatively correlated with interval times, but not surgical times or disease onset. Moreover, the activation marker, CD40 and CD86 was significantly up-regulated on the surfaces of mDC in JORRP patients compared with healthy controls. Neither the percentage nor activation of plasmacytoid DC (pDC) showed statistical difference between JORRP patients and healthy controls. HLA-DR expression on both mDC and pDC was down-regulated in JORRP group and negatively correlated with surgical times. Antigen presenting ability of DC was greatly impaired in JORRP patients of higher number of operations and shorter interval time. Plasma IL-10 as well as IL-10 secreted by mDC was higher in JORRP patients compared with healthy control. Finally, we detected an up-regulated TLR2 and TLR4 expression on mDCs and TLR4 expression was positively correlated with HLA-DR expression on mDC of JORRP patients.
Our results demonstrate an abnormal TLR2 and TLR4 expression in mDCs may contribute to suppressive immune response to HPV6 or HPV11 infection and associated with disease activity in JORRP patients.

Human papillomavirus causes various skin diseases and even cancer. Unfortunately, the host immune system often fails to generate effective responses against HPV infection due to the ability of HPV to evade immune-mediated eradication, although the detailed mechanisms by which HPV inhibits host antiviral immunity are not fully understood. In this study, we reported a novel role of HPV E7 oncoprotein in inducing the expression of co-inhibitory molecule cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) in cells of epithelial origin. Mechanistically, HPV E7 protein downregulated the cellular abundance of Jumonji C histone demethylase 1B (JHDM1B), increasing the levels of H3K36 methylation within the promoter region of CTLA-4. Our findings expand the current understanding of HPV-mediated immune evasion mechanisms and may be helpful in developing optimal anti-HPV therapeutic strategies and relevant drugs.

The aim of the present study was to investigate the correlation between human papillomavirus (HPV) type 6/11 and 16/18 infections and glandular thickening mammary gland hyperplasia in order to explore methods for preventing glandular thickening mammary gland hyperplasia. A total of 240 patients with glandular thickening mammary gland hyperplasia who were treated by surgery in our hospital from January 2012 to June 2017 were enrolled in the present study. The hyperplastic breast tissue and adjacent normal breast tissue were taken to test HPV type 6/11 and 16/18 infections using conventional PCR and in situ hybridization techniques. The correlations between HPV type 6/11 and 16/18 infections and glandular thickening mammary gland hyperplasia were analyzed using statistical methods of chi-square test. The infection rates of HPV type 6/11 and 16/18 in the hyperplastic breast tissue were 31.95% and 34.91%, respectively and 11.83% and 14.79% in the normal breast tissue, respectively. The differences were statistically significant (all p<0.05). HPV type 6/11 and 16/18 infections may be closely related to the development of glandular thickening mammary gland hyperplasia, and may be one of the causes of glandular thickening mammary gland hyperplasia.

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