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Recurrent respiratory papillomatosis (RRP) is a rare, proliferative disease caused by human papillomavirus 6 (HPV6) and HPV11. RRP can occasionally spread and undergo malignant transformation.We analysed samples across time for five RRP patients with malignant transformation and four with highly recurrent, non-malignant RRP by applying high-throughput sequencing.Patients with malignant transformation were infected by HPV11_A1/A2, while most non-malignant cases were associated with HPV6. Transient multiple infections with HPV6 and HPV11 were found in two patients, and resolved later to single infections. Viral genome loads were homogeneous across groups (median = 78 viral genomes per human genome). Within-patient, we did not observe differences between the viral sequences in the papillomatous lesions and in the malignant tissue. Genetic analysis of the NLRP1 gene revealed no known mutations linked to idiopathic RRP, though some novel variants merit to be explored in larger cohorts.HPV11 infections appear associated with RRP malignant transformation in young patients. Multiple infections can occur in RRP, but within-patient viral diversity is minimal for a given genotype. Our results confirm the importance of viral genotype in disease prognosis and are consistent with growing evidence of HPV11 infections to be differentially associated with RRP malignant transformation in young patients.

To better understand the natural history of anogenital warts (AGWs) and the dynamics of HPV6/11 infection in regional hairs, 32 newly diagnosed male patients with AGWs and 32 age-matched healthy controls were closely followed. During enrollment and six follow-up visits (every 2.6 months), 43 AGW tissues and 1232 anogenital and eyebrow hair samples were collected. This is the closest longitudinal monitoring of AGW patients to date. Patients were treated according to standards of care. The HPV6/11 prevalence was 19.9% in the patients' hair samples (HPV6 B1 in 53.1%) and 0% in the controls. The highest HPV6/11 prevalence was found in pubic hairs (29.0%) and the lowest in eyebrows (7.1%). The odds of having HPV6/11-positive hairs increased with smoking, shaving the anogenital region, and age. A close association between HPV6/11 presence in hairs and clinically visible AGWs was observed. The proportion of patients with visible AGWs and HPV6/11-positive hairs declined during follow-up with similar trends. No particular HPV6/11 variant was linked with an increased AGW recurrence, but the sublineage HPV6 B1 showed significantly higher clearance from hairs. Despite treatment, 78.1% and 62.5% of the AGW patients experienced one and two or more post-initial AGW episodes, respectively. The patients with HPV6/11-positive hairs or visible AGWs at a preceding visit demonstrated substantially higher odds of presenting with visible AGWs at a subsequent visit. [ABSTRACT FROM AUTHOR]

To better understand the natural history of anogenital warts (AGWs) and the dynamics of HPV6/11 infection in regional hairs, 32 newly diagnosed male patients with AGWs and 32 age-matched healthy controls were closely followed. During enrollment and six follow-up visits (every 2.6 months), 43 AGW tissues and 1232 anogenital and eyebrow hair samples were collected. This is the closest longitudinal monitoring of AGW patients to date. Patients were treated according to standards of care. The HPV6/11 prevalence was 19.9% in the patients’ hair samples (HPV6 B1 in 53.1%) and 0% in the controls. The highest HPV6/11 prevalence was found in pubic hairs (29.0%) and the lowest in eyebrows (7.1%). The odds of having HPV6/11-positive hairs increased with smoking, shaving the anogenital region, and age. A close association between HPV6/11 presence in hairs and clinically visible AGWs was observed. The proportion of patients with visible AGWs and HPV6/11-positive hairs declined during follow-up with similar trends. No particular HPV6/11 variant was linked with an increased AGW recurrence, but the sublineage HPV6 B1 showed significantly higher clearance from hairs. Despite treatment, 78.1% and 62.5% of the AGW patients experienced one and two or more post-initial AGW episodes, respectively. The patients with HPV6/11-positive hairs or visible AGWs at a preceding visit demonstrated substantially higher odds of presenting with visible AGWs at a subsequent visit.

The role of natural killer (NK) cells in juvenile-onset recurrent respiratory papillomatosis (JORRP) patients remains elusive. In this study, we find increased NK cell percentage, particularly CD11b-CD27- (DN) subsets in peripheral blood of JORRP patients and associated with disease activity. RNA sequencing shows a downregulated "natural killer cell-mediated cytotoxicity" feature in JORRP tumors. We also find impaired cytotoxic capacity and lower expression of NK cell-activating receptors including NKp30 and NKp46. Higher transforming growth factor-beta 1 (TGF-β1) is found both in plasma and tumor tissues of JORRP, and anti-TGF-β1 antibody could restore NK cell cytolytic activity and upregulate NKp30 and NKG2D expression. Also, we find a significantly higher Chemokine receptor type 6 (CXCR6) on NK cells in tumors compared with that in peripheral blood. Finally, RT-PCR analysis show that both HPV6-E6-E7 and HPV11-E6-E7 overexpression leads to higher TGFB1 expression compared with control SNU-1076 cell line, and higher CXCR6 expression is detected on NK coculture with HPV11-E6-E7-overexpressing cells. In conclusion, we demonstrate that TGF-β1 by papillomatosis leads to decreased NK cell cytotoxicity through downregulating NK cell-activating receptors in JORRP patients. [ABSTRACT FROM AUTHOR]

The role of natural killer (NK) cells in juvenile-onset recurrent respiratory papillomatosis (JORRP) patients remains elusive. In this study, we find increased NK cell percentage, particularly CD11b-CD27- (DN) subsets in peripheral blood of JORRP patients and associated with disease activity. RNA sequencing shows a downregulated “natural killer cell-mediated cytotoxicity” feature in JORRP tumors. We also find impaired cytotoxic capacity and lower expression of NK cell-activating receptors including NKp30 and NKp46. Higher transforming growth factor-beta 1 (TGF-β1) is found both in plasma and tumor tissues of JORRP, and anti-TGF-β1 antibody could restore NK cell cytolytic activity and upregulate NKp30 and NKG2D expression. Also, we find a significantly higher Chemokine receptor type 6 (CXCR6) on NK cells in tumors compared with that in peripheral blood. Finally, RT-PCR analysis show that both HPV6-E6-E7 and HPV11-E6-E7 overexpression leads to higher TGFB1 expression compared with control SNU-1076 cell line, and higher CXCR6 expression is detected on NK coculture with HPV11-E6-E7-overexpressing cells. In conclusion, we demonstrate that TGF-β1 by papillomatosis leads to decreased NK cell cytotoxicity through downregulating NK cell-activating receptors in JORRP patients.

Abstract Background Human papillomavirus type-6 (HPV6) is the major etiological agent of anogenital warts both men and women. The present study aimed to characterize the genetic diversity among HPV6 in Southwest China, and to investigate the origin of, selective pressure experienced by, and impact of the resultantly identified genetic variants on the HPV6 secondary structure. Methods Phylogenetic trees were constructed by Maximum-likelihood and the Kimura 2-parameters methods by Molecular Evolutionary Genetics Analysis version 6.0. The diversity of secondary structure was analyzed by PSIPred software. The selection pressures acting on the E6/E7 genes were estimated by Phylogenetic Analyses by Maximum Likelihood version 4.8 software. Results HPV6 was the most prevalent low risk HPV type in southwest China. In total, 143 E6 and E7 gene sequences of HPV6 isolated from patients were sequenced and compared to GenBank HPV6 reference sequence X00203. The results of these analyses revealed that both the HPV6 E6 and E7 were highly conserved within the analyzed patient samples, and comprised only 3 types of variant sequence, respectively. Furthermore, the analysis of HPV6 E6 and E7 sequences revealed seven/five single-nucleotide mutations, two/four and five/one of which were non-synonymous and synonymous, respectively. The phylogenetic analyses of the E6 and E7 sequences indicated that they belonged to sub-lineage A1 and sub-lineage B1, whereas the selective pressure analyses showed that only the E7 mutation sites 4R, 34E, and 52F were positive selection. Conclusions HPV6 (detection rate = 13.10%) was very prevalent in southwest China, both the HPV6 E6 and E7 sequences were highly conserved within the analyzed patient samples in southwest China, indicating that the low risk HPV6 can adapt to the environment well without much evolution.

Background: We studied the association between human papillomavirus (HPV) viral load (VL) and HPV concordance.Methods: The HITCH cohort study included young, heterosexual, recently formed, sexually active couples. Questionnaires and genital samples were collected at 0 and 4 months. Samples were tested for HPV DNA by polymerase chain reaction (PCR; Linear Array). VLs of HPV6/11/16/18/31/42/51 were quantified using type-specific real-time PCR. Correlations between VL and type-specific HPV prevalence and incidence were evaluated using multilevel, mixed-effects linear/logistic regression models.Results: We included 492 couples. VLs were higher in penile than vaginal samples. VL at subsequent visits correlated significantly within men (r, 0.373), within women (r, 0.193), and within couples (r range: 0.303-0.328). Men with high VL had more type-specific persistent HPV infections (odds ratio [OR], 4.6 [95% confidence interval {CI}, 2.0-10.5]). High VL in men was associated with prevalent (OR, 5.3 [95% CI, 2.5-11.2]) and incident (OR, 6.7 [95% CI, 1.5-30.7]) type-specific HPV infections in their partner. Women's VL was associated with type-specific HPV prevalence in their partner at the same (OR, 5.9) and subsequent (OR, 4.7) visit.Conclusions: Persistent HPV infections have limited VL fluctuations. VL between sex partners are correlated and seem predictive of transmission episodes. [ABSTRACT FROM AUTHOR]

Objective: Squamous cell carcinoma comprises approximately 94% of all oral cancers. One reason for this cancer is human papilloma virus (HPV) and its different genotypes. Determining the most common genotypes can assist with control and prevention of squamous cell carcinoma. Methods: We obtained 70 paraffin blocks from the Oncology Department at Imam Khomeini Hospital, Tehran, Iran. All samples included the histopathological report of dysplastic lesions. Samples were deparaffinated. Four primers were designed for PCR of samples. Positive samples were sequenced. Results: We have observed that 8 samples were HPV posetive, from which there were 3 HPV6 and 5 HPV16. HPV6 is one source for genital warts that can be spread by skin contact or oral-sexual behavior. There were 3 positive samples found in women, whereas the remainder were from men (2% more in men). People between the ages of 30 to 45 have increased sensitivity for HPV compared to the other group. People up to 60 years of age are also sensitive. All samples have been collected from different cities in Iran, however most of the positive samples were found in Tehran and Islam Shahr. Conclusion: These data confirmed that HPV infection with high risk types (6, 16) could be one of the risk factors for oral cancer which could be spread by genital warts. [ABSTRACT FROM AUTHOR]

Background Recurrent respiratory papillomatosis (RRP) is mainly associated with human papillomavirus (HPV)6 or HPV11. The purpose of this study was to compare clinical outcome, aggressiveness, and treatment response between HPV6- and HPV11-associated RRP. Methods A retrospective cohort of 55 patients with RRP (1974-2012) was used. Surgical interventions ( n = 814) were analyzed, and complications scored. HPV6/11-specific polymerase chain reaction (PCR) was performed on RRP biopsies. Results Seventy-six percent of patients (42 of 55) were infected with HPV6 and 24% (13 of 55) with HPV11. The HPV11 group had anatomically more widespread disease. The expected number of surgical interventions was higher in the younger age (<22.4 years) HPV11 group, and the older age (<22.4 years) HPV6 group. Regardless of HPV type, earlier age of onset of RRP resulted in a higher number of surgical interventions. Conclusion Anatomically, HPV11-associated RRP behaves more aggressively. Younger patients with HPV11 and older patients with HPV6 experience a worse clinical course of RRP. © 2014 Wiley Periodicals, Inc. Head Neck 37: 1625-1632, 2015 [ABSTRACT FROM AUTHOR]

Summary: Objectives: Human papillomavirus (HPV) types 6 and 11 are most commonly associated with ano-genital warts. There are few data on the sero-epidemiology of HPV6 and HPV11 among homosexual men. Methods: Behavioural data and sera for antibodies to HPV6 and HPV11 capsid protein L1 were collected annually for 1427 HIV negative and 245 HIV positive homosexual men. For HIV negative men, a combined variable, HPV6/11, was created (HPV 6 and/or 11) to analyse predictors of seroprevalence and seroincidence. Results: High rates of HPV6 and HPV11 seroprevalence were found (39.2–53.2% of men). For HPV6/11 (HIV negative men only), seroprevalence was associated with higher numbers of sexual partners, longer history of sexual activity and seropositivity for several sexually transmissible infections. Each year, 12.6% of men younger than 25 years seroconverted. Seroincidence (5.9/100PY) was associated with younger age, more recent male sexual partners, receptive anal fingering and anal chlamydia. Seropositivity and seroconversion were strongly associated with past and incident anal warts. Conclusions: HPV6 and HPV11 seropositivity were common among homosexual men. Among HIV negative men, HPV6/11 seroprevalence and seroincidence correlated closely with markers of sexual activity. The high numbers of young men seroconverting each year suggests a role for prophylactic vaccination of young gay men. Summary: Ano-genital warts, caused by human papillomavirus, are very common. In a community cohort of Australian homosexual men, HPV6 and 11 seroprevalence and seroincidence were high and were associated with past and incident anal warts and other markers of sexual activity. [Copyright &y& Elsevier]

Abstract: Objective: Human Papillomavirus (HPV) 6 and 11 are the aetiological agents responsible for Recurrent Respiratory Papillomatosis (RRP). There is general consensus that HPV11 results in more aggressive disease compared to HPV6. Method: Pubmed was searched using the terms respiratory papillomatosis, HPV 6 and HPV11. Comparisons were made in the outcomes of HPV6 versus HPV11 positive RRP disease. Results: There are numerous sub-types or variants of both HPV6 and HPV11. These sub-types have different activities at least in-vitro. The numbers of different HPV types within RRP tissue may be more extensive than initially appeared. This depends specifically upon the HPV types tested for. Conclusion: The clinical differences between HPV6 and HPV11 disease may not be accurately predictable as these viruses exist in numerous sub-types. Also, RRP tissue may contain more than one subtype or even be co-infected with other viruses that may influence outcome. In-vitro studies upon cell lines are a reasonable starting point for evaluation of these differences. [Copyright &y& Elsevier]

Background. Cidofovir is a nucleoside analogue that is used off-license to treat recurrent respiratory papillomatosis (RRP) caused by HPV6/11. However, the effect of this drug upon low-risk HPV 6/11 gene expression is unknown. Methods. The expression of E6 was evaluated by RT-PCR in HPV-ve C33A cervical carcinoma cells stably transfected with both low- and high-risk HPV E6 cDNA's and in SiHa (HPV16+ve) cervical carcinoma cells after treatment with 2 doses and durations of exposure to cidofovir. Results. Compared to the vector only transcript, E6 RNA levels showed an 8-fold increase in low-risk and 20-fold increase in high-risk E6-expressing cells. High-risk E6 protein levels were also detected by Western blot in cidofovir-treated C33A Type16 E6-transfected cells. Conclusion. These data may indicate a potential rationale for increased risk of genetic instability and thus transformation due to drug-induced increase in the level of E6. © 2009 Wiley Periodicals, Inc. Head Neck, 2009 [ABSTRACT FROM AUTHOR]

Background. Cidofovir has been reported to have activity against human papillomavirus (HPV) type 16, but no laboratory studies have been performed on HPV type 6, the main cause of recurrent respiratory papillomatosis (RRP). Methods. HPV6b E6 cDNA-based C33A (non-HPV cervical carcinoma) cell line was produced. Two different doses of cidofovir were applied to parent C33A, C33AT6E6, and C33AT16E6 (HPV 16). Growth and flow cytometry analysis were performed. Results. Polymerase chain reaction confirmed HPV6 E6 expression in C33AT6E6 cells. High-dose cidofovir was found to be toxic to all cell lines. Low-dose exposure was found to be toxic to C33AT16E6 cells at 3 days, whereas C33A and C33AT6E6 showed minimal toxicity at 6 days and earlier recovery following drug withdrawal. Conclusions. Cidofovir showed nonspecific toxicity against all 3 cell lines tested. HPV16 E6 expressing cells were more sensitive than parent or HPV6 E6 expressing cells. Cidofovir has no selective advantage for the RRP-related HPV6 E6 expressing cell line. © 2007 Wiley Periodicals, Inc. Head Neck, 2007 [ABSTRACT FROM AUTHOR]