Cutaneous alpha, beta and gamma human papillomaviruses in relation to squamous cell carcinoma of the skin: a population-based study.

Human papillomavirus (HPV) infection is common worldwide and, in immunodeficient populations, may contribute to the pathogenesis of keratinocyte cancers, particularly squamous cell carcinomas (SCC). However, their role in SCC in the general population is less clear. We conducted a comprehensive analysis to investigate the independent effects of seropositivity for cutaneous alpha, beta and gamma HPV types on risk of SCC, and a meta-analysis of the available literature. In a population-based case-control study from New Hampshire, USA (n = 1,408), histologically confirmed SCC cases and controls were tested for L1 antibodies to alpha, beta and gamma cutaneous HPV types 2-5, 7-10, 15, 17, 20, 23, 24, 27b, 36, 38, 48-50, 57, 65, 75-77, 88, 92, 95, 96, 101, 103 and 107 using multiplex serology. An increasing risk of SCC with number of beta HPVs to which an individual tested positive was observed even among those seronegative for gamma types (p for trend = 0.016) with an odds ratio of 1.95 (95% confidence interval (CI) = 1.07-3.56) for four or more beta types positive. In a meta-analysis of six case-control studies, increased SCC risks in relation to beta HPV seropositivity were found across studies (meta odds ratio = 1.45, CI = 1.27-1.66). While the prevalence of gamma HPVs assayed was somewhat higher among SCC cases than controls, the association was only weakly evident among those seronegative for beta HPVs. Overall, the association between cutaneous HPVs and skin cancers appears to be specific to SCC and to genus beta HPVs in a general US population.

Sunlight exposure and cutaneous human papillomavirus seroreactivity in basal cell and squamous cell carcinomas of the skin.

BACKGROUND: Ultraviolet radiation exposure may interact synergistically with cutaneous human papillomavirus (HPV) infection in the development of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin. METHODS: To investigate differences in the risk of sunlight-associated BCC and SCC by cutaneous genus-specific HPV serostatus, a case-control study was conducted among 204 BCC and 156 SCC cases who were recruited from a university dermatology clinic and 297 controls who had no history of cancer and screened negative for current skin cancer. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between measures of sunlight exposure and BCC/SCC, stratified by genus-specific HPV serostatus, with adjustment for age and sex. RESULTS: Sunburn due to cutaneous sensitivity to sunlight exposure (P = .006) and poor tanning ability (P = .003) were associated with a higher seroprevalence for genus beta HPV types. Poor or no tanning ability was more strongly associated with SCC among individuals who were seropositive for antibodies to cutaneous HPV types in genera alpha (OR, 15.60; 95% CI, 5.40-45.1; P = .01 for interaction) and beta (OR, 6.86; 95% CI, 3.68-12.80; P = .001 for interaction), compared with individuals who were seronegative for these HPV types. CONCLUSIONS: Seropositivity for HPV types in genera alpha or beta increased the risk of SCC associated with poor tanning ability.

Prospective study of human papillomavirus seropositivity and risk of nonmelanoma skin cancer.

Cutaneous human papillomaviruses (HPVs) have been associated with squamous cell carcinoma (SCC) in case-control studies, but there are limited data from prospective studies assessing whether virus exposure predicts risk of future cancer development. Two major biobanks, the Southern Sweden Microbiology Biobank (1971-2003) and the Janus Biobank (1973-2003) in Norway, containing samples from 850,000 donors, were searched for incident skin cancer for up to 30 years using registry linkages. Altogether, 2,623 donors with samples taken before diagnosis of SCC or basal cell carcinoma (BCC) of the skin were identified. Prediagnostic samples and samples from 2,623 matched controls were tested for antibodies against 33 types of HPV. Baseline seropositivity to HPV types in genus ß species 2 was associated with SCC risk (odds ratio = 1.3, 95% confidence interval: 1.1, 1.7); this was also the case for samples taken more than 18 years before diagnosis (odds ratio = 1.8, 95% confidence interval: 1.1, 2.8). Type-specific persistent seropositivity entailed elevated point estimates for SCC risk for 29 HPV types and decreased point estimates for only 3 types. After multiple hypothesis adjustment, HPV 76 was significantly associated with SCC risk and HPV 9 with BCC risk. In summary, seropositivity for certain HPV types was associated with an increased risk for future development of SCC and BCC.

Risk factors for cutaneous human papillomavirus seroreactivity among patients undergoing skin cancer screening in Florida.

BACKGROUND: Little is known about the risk factors for cutaneous human papillomavirus (HPV) infection. METHODS: To investigate factors associated with cutaneous HPV seropositivity, we conducted a cross-sectional study of 411 patients undergoing routine skin cancer screening examinations. Serum antibodies were measured and evaluated for 36 cutaneous HPV types in the genera alpha, beta, gamma, mu, and nu. Associations of demographic and lifestyle factors with cutaneous HPV seropositivity were estimated using odds ratios and 95% confidence intervals calculated using logistic regression. RESULTS: The seroprevalence of 1 cutaneous HPV type was 96% and 90% for men and women, respectively. Seroprevalence was highest for HPV types 4 (46%), 1 (37%), and 8 (31%) in men and for types 4 (47%), 63 (34%), and 1 (33%) in women. Independent associations of demographic and skin cancer risk factors with genus-specific HPV seropositivity differed by sex. For example, white skin, inability to tan, and lifetime residency in Florida were factors associated with genus-specific HPV seropositivity in men. Heavy smoking, sunscreen use, and green eye color were associated with genus-specific HPV seropositivity in women. CONCLUSIONS: Seroreactivity to cutaneous HPV types was highly prevalent in our study population. Different risk factors were independently associated with genus-specific cutaneous HPV seropositivity in men and women.

Seroprevalence of 34 human papillomavirus types in the German general population.

The natural history of infections with many human papillomavirus (HPV) types is poorly understood. Here, we describe for the first time the age- and sex-dependent antibody prevalence for 29 cutaneous and five mucosal HPV types from 15 species within five phylogenetic genera (alpha, beta, gamma, mu, nu) in a general population. Sera from 1,797 German adults and children (758 males and 1,039 females) between 1 and 82 years (median 37 years) were analysed for antibodies to the major capsid protein L1 by Luminex-based multiplex serology. The first substantial HPV antibody reactions observed already in children and young adults are those to cutaneous types of the genera nu (HPV 41) and mu (HPV 1, 63). The antibody prevalence to mucosal high-risk types, most prominently HPV 16, was elevated after puberty in women but not in men and peaked between 25 and 34 years. Antibodies to beta and gamma papillomaviruses (PV) were rare in children and increased homogeneously with age, with prevalence peaks at 40 and 60 years in women and 50 and 70 years in men. Antibodies to cutaneous alpha PV showed a heterogeneous age distribution. In summary, these data suggest three major seroprevalence patterns for HPV of phylogenetically distinct genera: antibodies to mu and nu skin PV appear early in life, those to mucosal alpha PV in women after puberty, and antibodies to beta as well as to gamma skin PV accumulate later in life.

Seroprevalence and determinants of eight high-risk human papillomavirus types in homosexual men, heterosexual men, and women: a population-based study in Amsterdam.

BACKGROUND: To determine differences in the seroprevalence of high-risk human papillomavirus (hrHPV) types between men having sex with men (MSM), heterosexual men and women, we analyzed seroprevalence and risk factors for 8 hrHPV in the general population of Amsterdam, the Netherlands. METHODS: We interviewed 1349 inhabitants aged ≥17 years and tested sera for antibodies against L1 capsid proteins of 8 hrHPV using Luminex-based multiplex serology. Risk factors for hrHPV were determined by multivariate Poisson analysis. RESULTS: Seroprevalences for 8 hrHPV ranged from 13.1% for HPV-45 to 31.4% for HPV-35. Seropositivity for HPV-16 and HPV-18 was more common in women and MSM than in heterosexual men. HPV-16 and -18 were more common in subjects also having antibodies against other hrHPV types (prevalence rate ratio [PRR], 2.12, 95% confidence interval [CI] 1.52-2.97; and PRR, 2.00; 95% CI, 1.43-2.81, respectively) and/or herpes simplex virus type 2 (PRR, 1.69; 95% CI, 1.32-2.16; and PRR, 1.47; 95% CI, 1.13-1.92, respectively). HPV-18 was more common in persons with a history of sexually transmitted infections (STI) (PRR, 1.64; 95% CI, 1.20-2.25). HPV-35, -45, and -58 were more common in non-European ethnic groups. CONCLUSIONS: Prevalence of 8 hrHPV antibodies was high in the Amsterdam population, especially in MSM.

A case-control study of cutaneous squamous cell carcinoma among Caucasian organ transplant recipients: the role of antibodies against human papillomavirus and other risk factors.

A case-control study was conducted in 140 people with histology proven cutaneous squamous cell carcinoma (SCC) and 454 controls, nested within 2 cohorts of organ transplant recipients (OTR) recruited in London and Oxford between 2002 and 2006. All participants had a skin examination, completed a questionnaire and had serum tested for antibodies against the L1 antigen of 34 HPV types using Luminex technology. SCC was more common in men than women (odds ratio [OR] = 1.7, 95% confidence interval [CI]: 1.1-2.8, p = 0.02) and in people with susceptibility to burn easily (OR = 3.0, 95%CI: 1.9-4.8; p < 0.001). The risk increased with increasing age (p-trend < 0.001), increasing time since transplant (p-trend < 0.001), increasing self-reported number of sunburns as a child (p-trend < 0.001) and with the presence of viral warts (p < 0.001). As expected, antibodies against HPV 16 were associated with a self-reported history of an abnormal cervical smear among women (OR 5.1, 95%CI: 2.6-10.2) and antibodies against HPV 6 were associated with a self-reported history of genital warts (OR 4.0, 95%CI: 2.2-7.2). However, no clear associations between any of the HPV types examined (including cutaneous betaHPVs) and SCC were identified. For example, the seroprevalence of HPV 5 was 15% among cases and 9% among controls (p = 0.09) and the seroprevalence of HPV 8 was 23% among cases and 21% among controls (p = 0.6). Nor was seropositivity to multiple types associated with SCC. These serological data do not provide evidence for a role for HPV in the aetiology of cutaneous SCC among OTR in two UK-based populations.

Measures of cutaneous human papillomavirus infection in normal tissues as biomarkers of HPV in corresponding nonmelanoma skin cancers.

Cutaneous human papillomavirus (HPV) may be associated with the development of nonmelanoma skin cancer (NMSC), as suggested by reports of HPV DNA in NMSC tumors. HPV has also been investigated as an NMSC risk factor in epidemiologic studies, although findings vary across studies that used different biomarkers of HPV infection in normal tissues. To identify appropriate biomarkers for use in future epidemiologic studies, we conducted a sampling validation study. NMSC tumor tissue was obtained from 20 patients with pathology-confirmed basal or squamous cell carcinoma of the skin, in addition to several normal tissues, including eyebrow hairs, normal skin swabs obtained using multiple techniques, normal skin punch and shave biopsies, and serum for antibody measurement. Presence of cutaneous HPV DNA in tissues was measured with multiplex PCR using HPV type-specific primers and array primer extension (APEX) for HPV typing. Antibody detection was based on glutathione-S-transferase capture ELISA in combination with fluorescent bead technology. Using HPV DNA in tumor tissues as a gold standard, sensitivity and specificity were calculated for each measure of HPV infection in normal tissues. beta-Papillomavirus DNA was observed in tumor tissues in 60% of patients. The normal skin punch biopsy demonstrated optimal sensitivity (75%) and specificity (75%). Biomarkers obtained using less-invasive techniques demonstrated poor specificity when considered individually, although specificity improved when biomarkers were combined. Based on the current case series, the combinations of antibodies+eyebrow hairs or antibodies+eyebrow hairs+Dacron swabs are the optimal, minimally invasive markers of cutaneous HPV infection for use in epidemiologic studies.

Hepatitis C Virus Seroprevalence in Mongolian Women Assessed by a Novel Multiplex Antibody Detection Assay.

BACKGROUND: Hepatitis C virus (HCV) infection causes hepatocellular carcinoma and is an important cause of mortality in both industrialized and developing countries. We developed a single-step high-throughput multiplex serology assay for HCV antibody detection and determined HCV prevalence in a highly endemic country. METHODS: Five proteins (Core, NS3, NS4A, NS5A, NS5B) each from the three most common subtypes of HCV (1a, 1b, 2a) were recombinantly expressed and used as antigens in a multiplexed antibody detection assay. Multiplex HCV serology was validated with 432 reference sera whose HCV status was established by commercial ELISA, Western blot, and RNA assays. HCV antibodies were determined in 1,023 sera representative for the adult female population of Mongolia. RESULTS: In reference sera, detection of HCV (mostly Core and NS3) antibodies by multiplex serology showed 100% sensitivity and 99.6% specificity, and was in very good agreement with the commercial diagnostic assays (kappa, 0.96; 95% confidence interval, 0.92-0.99). The role of antibodies to NS4 and NS5 remains to be evaluated. In Mongolia, overall HCV antibody prevalence was 18.9% (17.8% when age-standardized to the world population). HCV seroprevalence increased with age from 10% in women <30 years to 32% in women ≥50 years, but was not related to sexual risk factors. CONCLUSIONS: The single-step high-throughput multiplex HCV serology assay performs similarly to conventional HCV antibody screening followed by secondary confirmation assays. A very high HCV seroprevalence was confirmed across all socio-economic groups in the female population of Mongolia. IMPACT: Multiplex HCV serology facilitates large seroepidemiologic studies of HCV infection.

Study of squamous cell carcinoma associated with syringofibroadenoma for 105 types of human papillomavirus and for all currently known types of polyomaviruses.

Syringofibroadenoma is a benign tumor of the eccrine glands. Few cases of association with squamous cell carcinoma (SCC) have been published in the literature. In one of them, infection by human papillomavirus (HPV) type-107 was detected and the authors postulated that the virus might play a carcinogenic role. We studied a case of syringofibroadenoma associated with an SCC on the back of the right hand of an immunocompetent 95-year-old man. The lesion showed strong diffuse cytoplasmic staining for cytokeratin (CK) AE1/AE3, CK5/6, and 34ßE12 in the areas of syringofibroadenoma and in the areas of SCC. The marker p63 was expressed by the lower two thirds of the epithelium of the syringofibroadenoma. Epithelial membrane antigen and CK18 were expressed only by the superficial layers of the syringofibroadenomatous epithelium. The carcinomatous areas were epithelial membrane antigen positive. MIB1, p16, and p53 were mainly expressed by the SCC areas. The lesion was negative for all mucosal and cutaneous genus α-HPV, and for cutaneous HPV from γ-, µ-, and ν-genera. In 3 repeated genotyping experiments analyzing DNA from 2 consecutive biopsy sections, ß-HPV-9, 20, 36, 47, and 75, as well as FA-22 and 51 were found only once in the 6 possible reactions. ß-HPV-8 and 96 were detected 2 and 4 times, respectively, indicating very low viral loads of these HPV types. None of 8 known polyomaviruses was identified. ß-globin positivity was present in each assay, confirming sufficient quality of analyzed DNA.

Detection and typing of cutaneous human papillomavirus types--a comparison of three different methods.

Cutaneous human papillomavirus (HPV) may play a role in the development of cutaneous squamous cell carcinoma. HPV copy numbers in cutaneous squamous cell carcinoma are very low and hence sensitive and reliable detection methods are important, particularly to examine the natural history of cutaneous HPV. In the present study, the presence of cutaneous HPV types was examined in 194 skin swabs and in a subgroup of 91 skin swabs, and compared using three different PCR based methods: (i) beta/gamma cutaneous HPV PCR reverse-line-blotting (BGC-PCR RLB), (ii) multiplex cutaneous papillomavirus genotyping (McPG) and (iii) FAP PCR. The HPV prevalence was 75% (68/91) with BGC-PCR RLB, 64% (124/194) with McPG and 72% (139/194) with FAP PCR. The agreement for the detection of HPV between the three methods in the subset of 91 samples was 73% (66/91; kappa=0.34) for BGC-PCR RLB and McPG, 75% (68/91; kappa=0.32) for BGC-PCR RLB and FAP PCR, and 69% (63/91; kappa=0.25) for McPG and FAP PCR. For McPG and FAP PCR, 194 specimens were tested in total, with an overall agreement of 66% (129/194; kappa=0.24) for the detection of HPV. The concordance between the three methods was moderate, which could be explained by different HPV types detectable with each method; the high number of multiple infections and the low viral copy number in human skin. Overall, many cutaneous HPV types were identified and multiple HPV types were found frequently in the human skin swabs.

Case-control study of cutaneous human papillomavirus infection in Basal cell carcinoma of the skin.

Genus-ß human papillomavirus (HPV) DNA has been detected in basal cell carcinoma (BCC) tumors, but most epidemiologic studies have not observed associations between genus-ß HPV seropositivity and BCC. A clinic-based case-control study was conducted to investigate cutaneous HPV infection in BCC. BCC cases (n=224) were recruited from a dermatology clinic, and controls (n=300) were patients who were screened negative for skin cancer. Antibodies against cutaneous HPV types in genera α, ß, γ, mu, and nu were measured, and tumors from a subset of BCC cases (n=195) were tested for HPV DNA. Overall associations were observed between BCC and seropositivity for HPV types in genus-α (odds ratio (OR)=1.61; 95% confidence interval (CI)=1.11-2.35), γ (OR=1.78; 95% CI=1.22-2.60), and mu (OR=1.56; 95% CI=1.06-2.30). BCC cases with ß-HPV DNA in their tumors were more likely to be ß-HPV seropositive than controls (OR=1.76; 95% CI=1.03-3.01), with type-specific associations observed for HPV8 and HPV23, whereas no association was observed between ß-HPV seropositivity and ß-HPV DNA-negative BCC. No concordance between seropositivity and tumor DNA status was observed for HPV types in genera α and γ. In conclusion, the combined serology and tumor DNA results suggest that ß HPV types may have a role in BCC. Additional studies of BCC that assess HPV types in multiple genera are needed.

Dried blood spot samples for seroepidemiology of infections with human papillomaviruses, Helicobacter pylori, Hepatitis C Virus, and JC Virus.

BACKGROUND: To establish antibody analysis from dried blood spots (DBS) on filter paper for seroepidemiologic infection and cancer association studies, we analyzed data from a population-based study in Mongolia. METHODS: Using multiplex serology, we analyzed 985 paired DBS and serum samples from the same donors for antibodies to 12 different proteins from four groups of infectious agents: human papillomaviruses (HPV), Helicobacter pylori (H. pylori), hepatitis C virus (HCV), and JC polyomavirus (JCV). RESULTS: Quantitative antibody reactivities in serum and DBS showed good correlation, with median correlation coefficients (Pearson R(2)) of 0.88 (range, 0.80-0.90) for high-titer (i.e., H. pylori, HCV, JCV) and 0.79 (range, 0.72-0.85) for low-titer antibodies (i.e., HPV). For high-titer antibodies, serum and DBS data were comparable (median slope of linear trend line, 1.14; range, 1.09-1.21), whereas for low-titer antibodies, DBS reactivities were lower than in serum (median slope, 0.54; range, 0.50-0.80). By extrapolating seropositivity cutoff points previously defined for serum to DBS, we found high agreement (>89% for all antigens) of dichotomized DBS and serum results and median kappa values for high- and low-titer antibodies of 0.86 and 0.78 (range, 0.78-0.92 and 0.55-0.86), respectively. Epidemiologic associations with known risk factors for HPV antibodies were as strong for DBS as for serum. CONCLUSIONS: DBS provide a reliable alternative to serum or plasma for detection of antibodies against various pathogens by multiplex serology. IMPACT: DBS do not require blood centrifugation and allow storage and shipment at ambient temperature, thus facilitating field work for seroepidemiologic studies especially in environments with limited technical infrastructure.

Case-control study of cutaneous human papillomaviruses in squamous cell carcinoma of the skin.

BACKGROUND: Cutaneous human papillomavirus (HPV) infection may be a risk factor for squamous cell carcinoma (SCC) of the skin. METHODS: To investigate the association between cutaneous HPV and SCC, a case-control study was conducted, including 173 SCC cases from a university dermatology clinic and 300 controls that screened negative for skin cancer. Serum antibodies against cutaneous HPV types in genera alpha, beta, gamma, mu, and nu were measured. Tumor tissue from 159 SCC cases was tested for the presence of DNA for genus-beta HPV types. Using logistic regression ORs and 95% confidence intervals (CI) were estimated for the associations between SCC and cutaneous HPV infection, adjusting for age and sex. The Bonferroni method was used to account for multiple comparisons. RESULTS: SCC was positively associated with seropositivity to any genus-beta HPV type (OR, 1.93; 95% CI, 1.23-3.02), particularly with types in species-1 (OR, 1.86; 95% CI, 1.22-2.85). Type-specific associations with SCC were observed for HPV 8 (OR, 1.80; 95% CI, 1.14-2.84), 17 (OR, 1.59; 95% CI, 1.02-2.49) and HPV 10 from genus-alpha (OR, 2.24; 95% CI, 1.04-4.85). None of the type-specific associations remained statistically significant after correction for multiple comparisons. When DNA-positive SCC cases were compared with controls, strong serologic associations were observed for HPVs 5 (OR, 3.48; 95% CI, 1.27-9.59), 17 (OR, 3.36; 95% CI, 1.29-8.72), and 24 (OR, 3.79; 95% CI, 1.24-11.5). CONCLUSION: Genus-beta HPV infections were associated with SCC in our study population. IMPACT: Identifying the role of cutaneous HPV infection in SCC may lead to improved characterization of high-risk individuals and the development of novel prevention strategies.

Case-control study of Merkel cell polyomavirus infection and cutaneous squamous cell carcinoma.

BACKGROUND: Merkel cell polyomavirus (MCV) DNA has been reported in 0% to 25% of squamous cell carcinomas (SCC) occurring in immunocompetent individuals. We conducted the first serologic case-control study of MCV and SCC. METHODS: Patients with histologically confirmed cutaneous SCC (n = 173) were recruited from a university dermatology clinic. Controls were individuals who screened negative for and had no history of skin or other cancers (n = 300). Levels of antibodies against capsid antigens for MCV and another polyomavirus, JC virus (JCV), were determined by fluorescent bead-based multiplex serology. Fresh-frozen tumor tissues were obtained from 145 SCC cases and tested for MCV DNA by multiplexed PCR. Associations between MCV seroreactivity and SCC were estimated by ORs and 95% CIs calculated using logistic regression with adjustment for age and sex. RESULTS: MCV DNA was detected in SCC tumor tissues from 55 (38%) of 145 cases. A statistically significant association was observed between MCV seropositivity and MCV DNA-positive SCC (OR = 2.49, 95% CI = 1.03-6.04), with an almost four-fold association observed when comparing those with MCV antibodies in the fourth versus first quartiles (OR = 3.93, 95% CI = 1.43-10.76, P(trend) = 0.01). No significant associations were observed between MCV seropositivity and MCV DNA-negative SCC (OR = 1.38, 95% CI = 0.76-2.48) or between JCV seropositivity and MCV DNA-positive or DNA-negative SCC. CONCLUSION: Past exposure to MCV may be a risk factor for SCC. IMPACT: Understanding the role of viral infections in the development of nonmelanoma skin cancer could lead to novel prevention strategies.

Seroreactivity of 38 human papillomavirus types in epidermodysplasia verruciformis patients, relatives, and controls.

Epidermodysplasia verruciformis (EV) is a rare recessive genodermatosis characterized by high susceptibility to infections with human papillomaviruses (HPVs) of genus beta. Knowledge about seroreactivity against HPV in these patients and their first-degree relatives is scarce. Using multiplex serology, we analyzed antibodies to 38 HPV types from five genera in 32 EV patients, 22 first-degree relatives, and 64 and 44 age- and sex-matched, non-related, healthy controls, respectively. EV patients showed higher seroprevalences than non-related controls with statistically significant odds ratios (ORs) for 5 of 10 investigated alpha (OR range 6.9-21.3), all 16 beta (OR range 12.3-61.3), 3 of 9 gamma (OR range 6.4-11.7), and 1 of 2 micro HPVs (OR 5.8). In comparison to their relatives, antibodies in EV patients were significantly more prevalent for 4 of 16 beta HPVs (OR range 12.5-25.6), but for none of the other genera. A significantly increased seroprevalence in relatives compared with their controls was only seen for HPV 5 (OR 22.1). The considerably elevated HPV seroprevalence in EV patients, especially for beta papillomaviruses (PVs), reflects the high viral load described for these individuals. Whether the observed differences between relatives and healthy controls depend on heterozygosity for EV-associated alleles requires further investigation.

Virus-like particles and capsomeres are potent vaccines against cutaneous alpha HPVs.

The potential as prophylactic vaccines of L1-based particles from cutaneous genus alpha human papillomavirus (HPV) types has not been assessed so far. However, there is a high medical need for such vaccines since HPV-induced skin warts represent a major burden for children and for immunocompromised adults, such as organ transplant recipients. In this study, we have examined the immunogenicity of capsomeres and virus-like particles (VLPs) from HPV types 2, 27, and 57, the most frequent causative agents of skin warts. Immunization of mice induced immune responses resembling those observed upon vaccination with HPV 16 L1-based antigens. The antibody responses were cross-reactive but type-restricted in their neutralizing capacities. Application of adjuvant led to an enhanced potential to neutralize the respective immunogen type but did not improve cross-neutralization. Vaccination with capsomeres and VLPs from all four analyzed HPV types induced robust IFNgamma-associated T-cell activation. Immunization with mixed VLPs from HPV types 2, 27, and 57 triggered an antibody response similar to that after single-type immunization and capable of efficiently neutralizing all three types. Our results imply that vaccination with combinations of VLPs from cutaneous HPV types constitutes a promising strategy to prevent HPV-induced skin lesions.

Genus beta human papillomaviruses and incidence of basal cell and squamous cell carcinomas of skin: population based case-control study.

OBJECTIVE: To investigate the association between genus beta human papillomaviruses and the incidence of non-melanocytic skin cancer in the general population. DESIGN: Population based case-control study. SETTING: New Hampshire, USA. PARTICIPANTS: 2366 skin cancer cases and controls from the general population aged 25 to 74 years (663 squamous cell carcinoma, 898 basal cell carcinoma, 805 controls), with plasma samples tested for L1 antibodies to 16 genus beta human papillomaviruses by multiplex serology. MAIN OUTCOME MEASURES: Odds ratios for squamous cell carcinoma and basal cell carcinoma associated with seropositivity to beta human papillomaviruses. RESULTS: Squamous cell carcinoma, but not basal cell carcinoma, cases had a higher prevalence of each of the individual beta human papillomaviruses assayed compared with controls. The odds ratios for squamous cell carcinoma increased with the number of beta types positive (odds ratio for one type positive 0.99 (95% confidence interval 0.74 to 1.33); two to three types positive 1.44 (1.03 to 2.01); four to eight types positive 1.51 (1.03 to 2.20); more than eight types positive 1.71 (1.12 to 2.62); P for trend (categorical)<0.001; P for trend (continuous)=0.003). With limited statistical power, the association was stronger among long term users of systemic glucocorticoids (odds ratio 3.21, 1.22 to 8.44) than among non-users (1.23, 0.97 to 1.55). CONCLUSIONS: These findings support a relation between genus beta human papillomavirus infection and the incidence of squamous cell carcinoma of the skin in the general population, as well as potential enhancement of risk by immunosuppression.

The seroprevalence of human papillomavirus by immune status and by ethnicity in London.

BACKGROUND: The natural history of cutaneous HPV is unclear and in particular, seroprevalence among individuals with different levels of immune function and ethnicity is unknown. As part of a study of cutaneous squamous cell carcinoma (SCC) and HPV among organ transplant recipients (OTR) from London, we investigated the seroprevalence and risk factors for 34 HPV types (detected using Luminex technology) among 409 OTR patients without skin cancer (243 Caucasians and 166 non-Caucasians), 367 individuals with end stage renal failure on dialysis (222 Caucasians and 145 non-Caucasians) and 152 immunocompetent (IC) individuals without skin cancer (102 Caucasians and 50 non-Caucasians) to compare the HPV seroprevalence in patients with differing immune status and ethnicity. In total, seroprevalence data from 928 individuals, all from London, was available. RESULTS: Overall, no difference between HPV seroprevalence by immune status was observed (P = 0.3) among Caucasian or among non-Caucasian individuals, with seroprevalence varying from 87% to 94% across different immune status and ethnic groups. Those individuals seropositive to multiple types of one genus were more likely to be seroreactive to multiple types of another genus, independent of immune status or ethnicity. Lower seroprevalence for gammaHPV 4, and to a lesser extent gammaHPV 48, were observed among OTR compared to IC and dialysis patients. Higher seroprevalence against antibodies to betaHPV 93 were detected more frequently in non-Caucasians than Caucasians whereas muHPV 1 and, to a lesser extent, gammaHPV 4 were found more frequently among Caucasians - these findings were independent of immune status. Within non-Caucasian subgroups, the seroprevalence of 8 HPV (alpha-mucosal HPV16 and 13, alpha-cutaneous HPV7 and 2, betaHPV8, 17, 23 and 38) was significantly (P < 0.02) higher in Black compared to Asian patients. HPV16 being sexually transmitted, this might suggest a potential sexual route of transmission for some beta HPV types. CONCLUSION: We did not observe major disturbance in antibody response between immunocompetent, dialysis and OTR individuals, but significant differences in HPV seroprevalence were identified according to ethnicity. Further research is needed to clarify the natural history of cutaneous HPV, particularly given the growing research interest in its possible role in the pathogenesis of cutaneous SCC.

The sero-epidemiology of human papillomavirus among Caucasian transplant recipients in the UK.

BACKGROUND: Despite intensive study of high-risk mucosal human papillomaviruses (HPV), little is known of the epidemiology of cutaneous HPV. As part of a study of cutaneous squamous cell carcinoma and HPV among organ transplant recipients (OTR) from London and Oxford, we investigated the seroprevalence and risk factors for 34 HPV types (detected using Luminex technology) among 425 Caucasian OTR without skin cancer. RESULTS: Overall, 86% of participants were seropositive to at least one HPV: 41% to mucosal alpha types, 33% to cutaneous alpha types, 57% to alpha types, 56% to beta, 47% to gamma types and 45% to other types (nu, mu, HPV101 and 103). In both centres, the most common types were HPV6 (33% and 26% for London and Oxford respectively), HPV8 (24% and 18%), HPV15 (26% and 29%), HPV17 (25% and 21%), HPV38 (23% and 21%), HPV49 (19% and 21%), HPV4 (27% and 23%), HPV65 (30% and 25%), HPV95 (22% and 20%), HPV1 (33% and 24%) and HPV63 (28% and 17%). The seroprevalence of 8 HPV types differed significantly (P < 0.05) between London and Oxford. Those individuals seropositive to multiple types of one genus were more likely to be seroreactive to multiple types of another genus. As expected, antibodies against mucosal alphaHPV types were more frequent in younger patients and among women. Sunbed use and sunbathing was associated with seropositivity to multiple gammaHPV (P-trend = 0.007) and self-history of abnormal smear was related to seroactivity to multiple betaHPV (P = 0.01). Skin type and other self reported markers of exposure to ultraviolet radiation were not consistently associated with any HPV types. No other distinguishing epidemiological features of transplant recipients with antibodies against single or multiple HPV types were identified. CONCLUSION: Findings for mucosal HPV types were in line with results from previous studies. We observed differences in HPV seroprevalence between organ transplant recipients from two geographically close centres but no clear risk factor was found associated with cutaneous HPV seropositivity among organ transplant recipients. These findings have implications for interpretation of future seroepidemiology studies addressing the association between HPV and cutaneous SCC in OTR populations.