HPV-Associated Benign Squamous Cell Papillomas in the Upper Aero-Digestive Tract and Their Malignant Potential

Squamous cell papilloma (SCP) in the upper aero-digestive tract is a rare disease entity with bimodal age presentation both at childhood and in adults. It originates from stratified squamous and/or respiratory epithelium. Traditionally, SCPs have been linked to chemical or mechanical irritation but, since the 1980s, they have also been associated with human papillomavirus (HPV) infection. Approximately 30% of the head and neck SCPs are associated with HPV infection, with this association being highest for laryngeal papillomas (76-94%), followed by oral (27-48%), sinonasal (25-40%), and oropharyngeal papillomas (6-7%). There is, however, a wide variation in HPV prevalence, the highest being in esophageal SCPs (11-57%). HPV6 and HPV11 are the two main HPV genotypes present, but these are also high-risk HPVs as they are infrequently detected. Some 20% of the oral and oropharyngeal papillomas also contain cutaneous HPV genotypes. Despite their benign morphology, some SCPs tend to recur and even undergo malignant transformation. The highest malignant potential is associated with sinonasal inverted papillomas (7-11%). This review discusses the evidence regarding HPV etiology of benign SCPs in the upper aero-digestive tract and their HPV-related malignant transformation. In addition, studies on HPV exposure at an early age are discussed, as are the animal models shedding light on HPV transmission, viral latency, and its reactivation

Regulation of cell cycles is of key importance in human papillomavirus (HPV)-associated cervical carcinogenesis

The rapid progress in molecular biology has allowed the identification of the genes involved in different functions of normal cells and has also improved our understanding of the mechanisms of human carcinogenesis. The human papillomavirus (HPV) is a small double-stranded DNA tumor virus and its genes can manipulate cell cycle control to promote viral persistence and replication. The E6 and E7 proteins of high-risk HPV bind to cell cycle regulatory proteins and interfere with both G1/S and G2/M cell cycle checkpoints much more effectively than the low-risk HPV. The difference between the ability of low and high-risk HPV types to induce immortalization and transformation may well lie in their abilities to interact with the various cell cycle components, resulting in the loss of multiple cell cycle checkpoints, which are important in host genome fidelity, thus potentially resulting in accumulation of genetic abnormalities. Cervical cancer is one of the leading malignancies in women worldwide, with substantial morbidity and mortality. According to current concepts, HPV is recognized as the single most important causal agent in the pathogenesis of this cancer. HPV infection clearly precedes the development of malignancy, while being regularly associated with cervical cancer precursor lesions (all grades of squamous intraepithelial lesions). HPV-infected low-grade squamous intraepithelial lesion (SIL) has three possible outcomes: a) it may regress; b) it can persist; or c) it can make a clinical progression to in situ or invasive carcinoma. It has been well established by prospective cohort studies that the spontaneous regression rate increases in parallel with follow-up duration. In contrast, the clinical progression of lesions usually takes place quite rapidly, i.e. during the first two years from diagnosis. The mechanisms responsible for this divergent clinical behavior of HPV-associated squamous intraepithelial lesions are largely unknown, but currently under intense study in different laboratories worldwide

Optional screening strategies for cervical cancer using standalone tests and their combinations among low- and medium-income populations in Latin America and Eastern Europe

The performance of cervical cancer (CC) screening can be improved by combining Pap smear with human papillomavirus (HPV) testing or visual methods, addressing local demographic, clinical and economic characteristics.The NIS Cohort study was supported by the INCO-CopernicusProgramoftheEuropeanCommission(Contract No. ERB IC15-CT98 – 0321), and the LAMSstudy by the European Commission, INCO-DEV Program(Contract# ICA4-CT-2001 – 10013). We express specialthanks to the former Digene Corp. for providing theHybrid Capture analyser, samplers and the test kits at ourdisposal. We express our thanks to all women who partici-pated in these two cohort studies. Finally, all the membersof the NIS and LAMS Study research groups are acknowl-edged for their invaluable contribution to these studies

Outcomes of HPV type-specific serostatus do not associate with oral or genital HPV-carriage in non-vaccinated women followed for three years

BackgroundThe role of human papillomavirus (HPV) antibodies acquired through natural infection and their role in protection for subsequent cervical or oral HPV-carriage remains unclear.MethodsA total of 267 women, with a 36-months follow-up, from the Finnish Family HPV (FFHPV) study were evaluated to shed more light on persistent HPV-specific antibodies to genital or oral HPV-carriage, clearance or persistence during the three years follow-up. The type-specific seroprevalence for HPV genotypes 6, 11, 16, 18 and 45 in these women was assessed in relation to the detection of the same genotype or any HPV in their oral and genital samples. The following HPV serological outcomes where detected: being always seronegative, seroconversion or persistent seropositivity.ResultsGenital HPV16 infections were most prevalent at the end of the follow-up (24- and 36-month visit) among women who tested always seronegative for HPV16. No such associations between serology and HPV detection were established for the other HPV genotypes in the genital or oral samples. The development of long-term type-specific HPV 6,11,16,18 and 45 persistence (>= 24 months) or clearance of the genital or oral infections was not different among the women with high HPV genotype specific antibody levels and those testing always HPV-seronegative.ConclusionNo significant role was disclosed for the acquired natural high-level- or persistent HPV antibodies as determinants of the genital or oral HPV infection outcomes in these young, non-vaccinated women.</p

Outcomes of HPV type-specific serostatus do not associate with oral or genital HPV-carriage in non-vaccinated women followed for three years

Background: The role of human papillomavirus (HPV) antibodies acquired through natural infection and their role in protection for subsequent cervical or oral HPV-carriage remains unclear. Methods: A total of 267 women, with a 36-months follow-up, from the Finnish Family HPV (FFHPV) study were evaluated to shed more light on persistent HPV-specific antibodies to genital or oral HPV-carriage, clearance or persistence during the three years follow-up. The type-specific seroprevalence for HPV genotypes 6, 11, 16, 18 and 45 in these women was assessed in relation to the detection of the same genotype or any HPV in their oral and genital samples. The following HPV serological outcomes where detected: being always seronegative, seroconversion or persistent seropositivity. Results: Genital HPV16 infections were most prevalent at the end of the follow-up (24- and 36-month visit) among women who tested always seronegative for HPV16. No such associations between serology and HPV detection were established for the other HPV genotypes in the genital or oral samples. The development of long-term type-specific HPV 6,11,16,18 and 45 persistence (≥ 24 months) or clearance of the genital or oral infections was not different among the women with high HPV genotype specific antibody levels and those testing always HPV-seronegative. Conclusion: No significant role was disclosed for the acquired natural high-level- or persistent HPV antibodies as determinants of the genital or oral HPV infection outcomes in these young, non-vaccinated women.publishedVersionPeer reviewe

Interferon-gamma and IL-5 associated cell-mediated immune responses to HPV16 E2 and E6 distinguish between persistent oral HPV16 infections and noninfected mucosa

Objectives: Natural history of human papillomavirus (HPV) infection in the head and neck region is poorly understood, and their impact on collective HPV-specific immunity is not known. Materials and methods: In this study, we have performed a systematic analysis of HPV16-specific cell-mediated immunity (CMI) in 21 women with known oral and genital HPV DNA status and HPV serology (Ab) based on 6-year follow-up data. These women being a subgroup from the Finnish Family HPV Study were recalled for blood sampling to be tested for their CMI-responses to HPV16 E2, E6, and E7 peptides. Results: The results showed that HPV16 E2-specific lymphocyte proliferation was more prevalent in women who tested HPV16 DNA negative in oral mucosa and were either HPV16 seropositive or negative than in HPV16 DNA+/Ab+ women (p = 0.046 and p = 0.035). In addition, the HPV16 DNA-/Ab- women most often displayed E6-specific proliferation (p = 0.020). Proportional cytokine profiles indicated that oral HPV16-negative women were characterized by prominent IFN-gamma and IL-5 secretion not found in women with persisting oral HPV16 (p = 0.014 and p = 0.040, respectively). Conclusions: Our results indicate that the naturally arising immune response induced by oral HPV infections displays a mixed Th1/Th2/Th17 cytokine profile while women with persisting oral HPV16 might have an impaired HPV16-specific CMI, shifted partly toward a Th2 profile, similarly as seen earlier among patients with high-grade genital HPV lesions. Thus, the lack of HPV 16 E2 and E6 specific T memory cells and Th2 cytokines might also predispose women for persistent oral HPV16 infection which might be related to the risk of cancer.Peer reviewe

Antisense RNA directed to the human papillomavirus type 16 E7 mRNA from herpes simplex virus type 1 derived vectors is expressed in CaSki cells and downregulates E7 mRNA

<p>Abstract</p> <p>Background</p> <p>Human papillomavirus (HPV) infection is known to be the most important etiologic factor of cervical cancer. There is no HPV specific therapy available for treatment of invasive squamous cell carcinoma of the cervix and its precursor lesions. The present study elucidates the potential to use herpes simplex virus (HSV) derived vectors for expression of antisense RNA to HPV -16 E7 oncogene.</p> <p>Results</p> <p>We have constructed replication competent, nonneuroinvasive HSV-1 vectors, deleted of the γ₁34.5 gene. The vectors express RNA antisense to the first 100 nucleotides of the HPV-16 E7 gene. We assayed the ability of the antisense E7 vectors R5225 (<it>tk</it>-) and R5226 (<it>tk+</it>), to produce antisense RNA, as well as the consequent effects on E7 mRNA and protein levels in HPV-16 positive CaSki cells. Anti-E7 RNA was expressed by both constructs in a dose-dependent manner. Expression of HPV-16 E7 mRNA was downregulated effectively in CaSki cells infected with the <it>tk- </it>recombinant R5225 or with R5226. The <it>tk+ </it>recombinant R5226 was effective in downregulating E7 protein expression.</p> <p>Conclusion</p> <p>We have shown that anti-E7 RNA expressed from an HSV vector could efficiently downregulate HPV-16 E7 mRNA and E7 protein expression in CaSki cells. We conclude that HSV vectors may become a useful tool for gene therapy of HPV infections.</p

Effect of a Second Pregnancy on the HPV Serology in Mothers Followed Up in the Finnish Family HPV Study

The impact of pregnancy on human papillomavirus (HPV) natural antibody levels is not fully understood. We tested the seroprevalence and levels of HPV 6, 11, 16, 18 and 45 antibodies at different time points among 89 women with a second pregnancy and 238 nonpregnant women during their 36-month followup. All participants were unvaccinated for HPV and pregnant at the enrollment of the study. Serum samples were collected from the mothers at baseline and at the 12-month, 24-month, and 36-month followup visits. No statistically significant differences in mean antibody levels were observed in women who developed a second pregnancy compared to their nonpregnant counterparts. Between these two groups, statistically significant differences in serostatus were observed, particularly if the second pregnancy was ongoing at the 24-month timepoint. Accordingly, women with a second pregnancy were more likely to be seronegative for HPV 6, 11, 18, and 45 as compared to the nonpregnant women, the reverse being true for HPV16. In contrast, the women with an ongoing second pregnancy showed a higher prevalence of HPV16 seropositivity at the 36-month followup. These data suggest that a second pregnancy does not seem to have a major impact on the levels of HPV antibodies, but it might influence the serological outcomes.Peer reviewe

Maternal HPV-antibodies and seroconversion to HPV in children during the first 3 years of life

To assess the dynamics of human papillomavirus (HPV) serology, we analyzed HPV6-,11-,16-,18-, and 45 antibodies in infants during the first 36 months of their life. Serial serum samples of 276/327 mother–child pairs were collected at baseline (mothers) and at months 1, 2, 6, 12, 24 and 36 (offspring), and tested for HPVL1-antibodies using the GST-L1 assay. Concordance between maternal and infant HPV-antibody levels remained high until month-6 (p < = 0.001), indicating maternal antibody transfer. At 1 month, 40–62% of the infants tested seropositive to any of the 5 HPV-types. Between 1–3 years of age, 53% (58/109) of the children born to HPV-seronegative mothers tested HPV-seropositive. Times to positive seroconversion varied between13.4 and 18.7 months, and times to negative seroconversion (decay) between 8.5 and 9.9 months. Significant independent predictors of infants’ seroconversion to LR-HPV were hand warts and mother’s history of oral warts and seroconversion to LR-HPV. No predictors of seroconversion to HR-HPV were identified. Maternal HPV-IgG-antibodies are transferred to her offspring and remain detectable for 6 months, corroborating the IgG molecule’s half-life. Seroconversion to HPV-genotypes 6, 11, 16 and 18 was confirmed among children born to HPV-seronegative mothers, implicating an immune response to these HPV-genotypes during early infancy.publishedVersionPeer reviewe