Sexual behaviours associated with incident high-risk anal human papillomavirus among gay and bisexual men.

OBJECTIVE: High-risk human papillomavirus (HRHPV) causes anal cancer, which disproportionately affects gay and bisexual men (GBM). We examined sexual behaviours associated with incident anal HRHPV in an observational cohort study of GBM in Sydney, Australia. METHODS: GBM aged 35 years and above were enrolled in the Study of the Prevention of Anal Cancer. Detailed information on sexual practices in the last 6 months, including receptive anal intercourse (RAI) and non-intercourse receptive anal practices, was collected. Anal human papillomavirus (HPV) testing was performed at the baseline and three annual follow-up visits. Risk factors for incident HRHPV were determined by Cox regression using the Wei-Lin-Weissfeld method. RESULTS: Between 2010 and 2015, 617 men were recruited and 525 who had valid HPV results at baseline and at least one follow-up visit were included in the analysis. The median age was 49 years (IQR 43-56) and 188 (35.8%) were HIV-positive. On univariable analysis, incident anal HRHPV was associated with being HIV-positive (p<0.001), having a higher number of recent RAI partners regardless of condom use (p<0.001 for both), preference for the receptive position during anal intercourse (p=0.014) and other non-intercourse receptive anal sexual practices, including rimming, fingering and receptive use of sex toys (p<0.05 for all). In multivariable analyses, being HIV-positive (HR 1.46, 95% CI 1.09 to 1.85, p=0.009) and reporting condom-protected RAI with a higher number of sexual partners (p<0.001) remained significantly associated with incident HRHPV. When stratified by recent RAI, non-intercourse receptive anal practices were not associated with incident HRHPV in men who reported no recent RAI. CONCLUSION: GBM living with HIV and those who reported RAI were at increased of incident anal HRHPV. Given the substantial risk of anal cancer and the difficulty in mitigating the risk of acquiring anal HRHPV, HPV vaccination should be considered among sexually active older GBM. TRIAL REGISTRATION NUMBER: ANZCTR365383.

Understanding the Role of Emerging Vitamin D Biomarkers on Short-term Persistence of High-Risk Human Papillomavirus Infection Among Mid-Adult Women.

BACKGROUND: Associations between vitamin D biomarkers and persistent high-risk human papillomavirus (hrHPV) detection have not been evaluated. METHODS: 2011-2012 stored sera from 72 women aged 30-50 years with prevalent hrHPV (n = 116 type-specific infections) were tested for 5 vitamin D biomarkers: 25(OH)D and 4 emerging biomarkers, 1,25(OH)2D; 24,25(OH)2D; free vitamin D; and vitamin D binding protein (DBP). The hrHPV detection patterns (persistent vs transient/sporadic) were determined using cervicovaginal swabs collected monthly for 6 months. Associations between vitamin D and short-term type-specific hrHPV persistence were estimated using logistic regression. Our primary exposure was continuous 25(OH)D, with additional biomarkers evaluated as secondary exposures. Primary models were adjusted for age, race, body mass index, education, contraceptives, smoking, season, and calcium/phosphate levels. Sensitivity analyses were restricted from 19 hrHPV types to 14 used in cervical cancer screening. RESULTS: In primary analyses, nonsignificant positive associations with hrHPV persistence were observed for measures of 25(OH)D and 24,25(OH)2D. Associations were stronger and significant when restricting to 14 hrHPV types (25(OH)D per 10 ng/mL increase: adjusted odds ratio [aOR], 1.82 [95% confidence interval {CI}, 1.15-2.88] and aOR, 4.19 [95% CI, 1.18-14.88] DBP-adjusted; 25(OH)D ≥30 vs <30 ng/mL: aOR, 8.85 [95% CI, 2.69-29.06]; 24,25(OH)2D: aOR, 1.85 [95% CI, 1.18-2.88]). 1,25(OH)2D was unassociated with persistence. CONCLUSIONS: Serum vitamin D measured by multiple biomarkers showed positive associations with short-term hrHPV persistence that were significant only when restricting to 14 clinically relevant hrHPV types.

Cutaneous viral infections associated with ultraviolet radiation exposure.

The complex interplay between ultraviolet radiation (UVR) and cutaneous viral infections in the context of cancer etiology is challenging to unravel, given the limited information on the independent association between UVR and cutaneous viral infections. Using multiple biomarkers of infection with 24 types of cutaneous human papillomavirus (HPV) and 4 types of polyomaviruses (HPyV), we investigated cross-sectional associations with recent UVR exposure, using skin pigmentation measured by spectrophotometer. Age- and sex-adjusted associations between UVR and viral seropositivity, viral DNA present in eyebrow hairs (EBH) and skin swabs (SSW) were estimated using logistic regression. Beta-HPV seropositivity was associated with viral DNA positivity in EBH (OR = 1.40, 95% CI = 1.05-1.88) and SSW (OR = 1.86, 95% CI = 1.25-2.74). Similar associations were observed for Merkel cell polyomavirus. Participants in the highest tertile of UVR exposure were more likely to be seropositive for beta-HPV (OR = 1.81, 95% CI = 1.16-2.38), and have beta-HPV DNA in EBH (OR = 1.57, 95% CI = 1.06-2.33) and SSW (OR = 2.22, 95% CI = 1.25-3.96), compared to participants with the lowest tertile of UVR exposure. UVR exposure was positively associated with three different markers of beta-HPV infection. Therefore, future studies of HPV associated KC development should address more directly the role of HPV and UVR exposure as potential co-carcinogens.

Conjunctival cancer in people living with HIV.

PURPOSE OF REVIEW: Historically, conjunctival cancer has been associated with HIV particularly in sub-Saharan Africa. The human papilloma virus (HPV) has been implicated as a potential causative agent without conclusive evidence. This review covers recent evidence of the epidemiology, diagnosis and treatment of conjunctival cancer in people living with HIV (PLWH). RECENT FINDINGS: HIV infection has been attributed to 33% of squamous cell carcinoma of the conjunctiva in sub-Saharan Africa. Although clear evidence of the effect of immunodeficiency on conjunctival cancer risk has been demonstrated, the role of HPV on conjunctival cancer development is still unclear. Biomarkers such as the p16 protein are not always indicative of HPV infection. The Epstein-Barr virus (EBV) might potentially be another infectious agent of interest in the development of conjunctival cancer. There is some evidence of increased conjunctival cancer recurrence post treatment as well as increased probability of metastasis in PLWH. SUMMARY: Immunodeficiency increases the risk of conjunctival cancer in PLWH. Symptomatic screening of conjunctival cancer in PLWH should be encouraged. Research on HPV involvement should remain a priority and EBV considered as another etiologic agent of interest. More studies on treatment modalities in PLWH should be considered.

Human papilloma viruses infection among adolescent females perinatally infected with HIV in Côte d'Ivoire.

BACKGROUND: Cervical cancer prevention strategies recommend human papilloma virus (HPV) vaccination for female adolescents prior to their sexual debut. While HIV is a major risk factor for HPV infection in women of childbearing age, its prevalence among HIV-infected adolescent female is mostly unknown. This study aimed to describe the HPV prevalence and correlates among perinatally HIV-infected adolescent females prior to HPV immunisation. METHODS: A cross-sectional survey was conducted from January to June 2016, in the four major paediatric HIV clinics of Abidjan, Côte d'Ivoire. All HIV-infected females aged 11-16 years were approached to participate in the study. A questionnaire assessing sexual behaviours and genital hygiene practices was administered to participants completed with a systematic vaginal swab collection. HPV genotyping was performed using the Anyplex II HPV28 Detection (Seegene). A logistic regression analysis was performed to identify factors associated with the presence of HPV infection. HPV immunisation was proposed free of charge to all participants. RESULTS: A total of 250 participants were included, with a median age of 13 years (IQR 11-14). Among them, 237 (94.8%) were on antiretroviral treatment with a median CD4 count of 660 (IQR 439-914) cells/mm3. The overall prevalence of at least one HPV was 3.6% (95% CI 1.6 to 6.7) and the prevalence of at least one carcinogenic HPV was 2.8% (95% CI 0.7 to 4.8). Vaginal cleansing was reported by 75 (30%) of participants, with a median age at initiation of 12 years (IQR 10-13). Sexual activity was self-reported by 12 (4.8%) participants with a median age at sexual debut of 11 years (IQR 10-14). HPV infection was associated with vaginal cleansing (adjusted OR=7.0 (95% CI 1.4 to 31.6)). CONCLUSION: The reported low prevalence of carcinogenic HPV infections supports the appropriateness of HPV immunisation in this population. The reported association between cleansing practices and HPV infection deserves further prospective longitudinal studies.

Prevalence of anal cytological abnormalities and high-risk human papillomavirus prevalence in kidney transplant recipients: A cross-sectional study.

BACKGROUND: Transplant recipients are at high-risk of anal squamous cell cancer. We aimed to estimate the prevalence of high-risk human papillomavirus (HPV) and high-grade squamous intraepithelial lesion (HSIL) and assess characteristics associated with results METHODS: We recruited kidney transplant recipients in a single-center, 2015-2018. Participants completed a clinical questionnaire and received an anal-swab sent for HPV-DNA and cytological testing RESULTS: A total of 97 (74%) of 125 recipients approached consented to participate. Participants were median 47 (IQR 40-55) years, 60% male and median 4.5 (IQR .9-13) months-since-transplant. Of 86 assessable samples, at least one HPV genotype was detected in 15 (17%) participants; 1 (1%) HPV16, 8 (9%) other high-risk HPV. Of 76 assessable cytology samples, 9 (12%) showed evidence of abnormality; 1 (1%) HSIL, 1 (1%) atypical-squamous-cells, cannot exclude HSIL. Both HSIL recipients had high-risk HPV and biopsy confirmed HSIL. High-risk HPV was detected in six (9%) recipients with normal cytology. History of sexually transmitted infection, and abnormal cervical pap smear in women, was associated with high-risk HPV and HSIL CONCLUSIONS: High-risk HPV and HSIL testing may identify kidney transplant recipients at higher risk of anal cancer. Longitudinal studies are needed to describe the natural history of anal cancer in transplant recipients.

Advances in Targeting HPV Infection as Potential Alternative Prophylactic Means.

Infection by oncogenic human papillomavirus (HPV) is the primary cause of cervical cancer and other anogenital cancers. The majority of cervical cancer cases occur in low- and middle- income countries (LMIC). Concurrent infection with Human Immunodeficiency Virus (HIV) further increases the risk of HPV infection and exacerbates disease onset and progression. Highly effective prophylactic vaccines do exist to combat HPV infection with the most common oncogenic types, but the accessibility to these in LMIC is severely limited due to cost, difficulties in accessing the target population, cultural issues, and maintenance of a cold chain. Alternative preventive measures against HPV infection that are more accessible and affordable are therefore also needed to control cervical cancer risk. There are several efforts in identifying such alternative prophylactics which target key molecules involved in early HPV infection events. This review summarizes the current knowledge of the initial steps in HPV infection, from host cell-surface engagement to cellular trafficking of the viral genome before arrival in the nucleus. The key molecules that can be potentially targeted are highlighted, and a discussion on their applicability as alternative preventive means against HPV infection, with a focus on LMIC, is presented.

Twelve-Year Trend in the Prevalence of High-Risk Human Papillomavirus Infection Among Rwandan Women Living With HIV.

BACKGROUND: We examined the trend in prevalence of high-risk human papillomavirus (hrHPV) cervical infection among Rwandan women living with HIV (WLWH) over 12 years. METHODS: Prevalence of cervical hrHPV DNA was measured in 3 studies at 3 different time periods in 3 different groups of WLWH using 3 different but comparable hrHPV tests: a MY09/MY11 PCR test in 2005 (RWISA; n = 497), careHPV in 2009-2010 (HPV Demonstration; n = 1242), and Xpert HPV test in 2016-2018 (U54; n = 4734). Prevalences were adjusted for age and CD4 cell count. RESULTS: HrHPV prevalence decreased over time from 42.5% to 32.2% to 26.5% (P < .001). CD4 cell counts improved over time (Ptrend <.001) so that the percentage of WLWH with CD4 counts of ≥500 cells/µL increased from 7.7% in 2005 to 42.2% in 2009-2010 and 61.1% in 2016-2018. Thus, after adjustment for differences in CD4 counts and age, hrHPV prevalences were more similar over time: 32.6% for RWISA, 30.6% for HPV Demonstration, and 27.1% for U54 (P = .007). CONCLUSIONS: Prevalence of hrHPV among WLWH has decreased over the past decade, most likely the result of improved immune reconstitution due to better HIV care and management in Rwanda.

Temporal changes in the vaginal microbiota in self-samples and its association with persistent HPV16 infection and CIN2.

BACKGROUND: The vaginal microbiota has been reported to be associated with HPV infection and cervical cancer. This study was performed to compare the vaginal microbiota at two timepoints in women performing self-sampling and had a persistent or transient HPV16 infection. The women were tested for 12 high-risk HPV (hrHPV) types but only women with single type (HPV16) were included to reduce confounding variables. METHODS: In total 96 women were included in this study. Of these, 26 were single positive for HPV16 in the baseline test and HPV negative in the follow-up test and 38 were single positive for HPV16 in both tests and diagnosed with CIN2+ in histology. In addition, 32 women that were negative for all 12 HPV tested were included. The samples of vaginal fluid were analyzed with the Ion 16S™ Metagenomics Kit and Ion 16S™ metagenomics module within the Ion Reporter™ software. RESULTS: K-means clustering resulted in two Lactobacillus-dominated groups, one with Lactobacillus sp. and the other specifically with Lactobacillus iners. The two remaining clusters were dominated by a mixed non-Lactobacillus microbiota. HPV negative women had lower prevalence (28%) of the non-Lactobacill dominant cluster in the baseline test, as compared to women with HPV16 infection (42%) (p value = 0.0173). Transition between clusters were more frequent in women with persistent HPV16 infection (34%) as compared in women who cleared the HPV16 infection (19%) (p value = 0.036). CONCLUSIONS: The vaginal microbiota showed a higher rate of transitioning between bacterial profiles in women with persistent HPV16 infection as compared to women with transient infection. This indicate an instability in the microenvironment in women with persistent HPV infection and development of CIN2+.

Prevalence of human papillomavirus-related diseases in the Republic of Korea: a cross-sectional study.

OBJECTIVE: We aimed to evaluate trends in the prevalence of human papillomavirus (HPV)-related diseases in the era before the introduction of organised HPV vaccination programmes in the Republic of Korea. METHODS: This cross-sectional study used National Health Insurance Service data from 2002 to 2015 and included participants who were diagnosed with the following HPV-related diseases (codes from the International Classification of Diseases, 10th Revision): genital warts (A63.0); cancer in the head and neck (C00-C10), anus (C21), vulva (C51), vagina (C52), cervix uteri (C53) and penis (C60); carcinoma in situ (CIS) of the lip/oral cavity/pharynx (D00.0), anus (D01.3), cervix (D06), vulva (D07.1), vagina (D07.2) and penis (D07.4); benign neoplasms of the larynx (D14.1); and dysplasia of the cervix (N87), vagina (N89) and vulva (N90). For each diagnosis, the fraction of cases attributable to HPV in Korea was assessed based on the percentages of diseases attributable to HPV reported in some international studies. The age-standardised prevalence was estimated using the direct population-based method. RESULTS: The overall age-standardised prevalence of HPV-related diseases increased from 2002 to 2015, mainly due to increased prevalence of genital warts in men and cervical dysplasia and CIS in women. In women, genital wart prevalence increased from 2002 (24.4 per 100 000) to 2011 (57.1) and then decreased until 2015 (53.5); in men, the prevalence increased steadily from 2002 (22.9) to 2015 (109.4). The prevalence of cervical dysplasia and CIS increased (from 86.5 in 2002 to 484.5 in 2015, and from 60.3 in 2002 to 114.9 in 2015, respectively), but that of cervical cancer decreased (from 120.0 in 2002 to 106.9 in 2015). CONCLUSIONS: Non-organised HPV vaccination and organised cervical cancer screening may have contributed to the downward trend in genital wart prevalence and the upward trend in cervical abnormalities among women.

Results from a cross-sectional sexual and reproductive health study among school girls in Tanzania: high prevalence of bacterial vaginosis.

OBJECTIVES: Bacterial vaginosis (BV) increases women's susceptibility to sexually transmitted infections (STIs) and HIV and may partly explain the high incidence of STI/HIV among girls and young women in East and southern Africa. The objectives of this study were to investigate the association between BV and sexual debut, to investigate other potential risk factors of BV and to estimate associations between BV and STIs. METHODS: Secondary school girls in Mwanza, aged 17 and 18 years, were invited to join a cross-sectional study. Consenting participants were interviewed and samples were obtained for STI and BV testing. Factors associated with prevalent BV were analysed using multivariable logistic regression. Y-chromosome was tested as a biomarker for unprotected penile-vaginal sex. RESULTS: Of the 386 girls who were enrolled, 163 (42%) reported having ever had penile-vaginal sex. Ninety-five (25%) girls had BV. The prevalence of BV was 33% and 19% among girls who reported or did not report having ever had penile-vaginal sex, respectively. BV was weakly associated with having ever had one sex partner (adjusted odds ratio (aOR) 1.59;95% CI 0.93 to 2.71) and strongly associated with two or more partners (aOR = 3.67; 95% CI 1.75 to 7.72), receptive oral sex (aOR 6.38; 95% CI 1.22 to 33.4) and having prevalent human papillomavirus infection (aOR = 1.73; 95% CI 1.02 to 2.95). Of the 223 girls who reported no penile-vaginal sex, 12 (5%) tested positive for an STI and 7 (3%) tested positive for Y-chromosome. Reclassifying these positive participants as having ever had sex did not change the key results. CONCLUSIONS: Tanzanian girls attending school had a high prevalence of BV. Increasing number of sex partner was associated with BV; however, 19% of girls who reported no penile-vaginal sex had BV. This suggests that penile-vaginal sexual exposure may not be a prerequisite for BV. There was evidence of under-reporting of sexual debut.

Warts and all: Fingolimod and unusual HPV-associated lesions.

BACKGROUND: Fingolimod is used to reduce relapse rates in relapsing-remitting multiple sclerosis (MS). It is a sphingosine 1-phosphate (S1P) analogue having antagonistic effects on S1P receptors. Its immunosuppressive effect is due to reduced circulating lymphocyte numbers, and it may also be associated with impaired intrinsic cancer surveillance. Fingolimod side effects include increased rates and severity of viral infections particularly varicella zoster. METHODS: We present five cases of chronic and treatment refractory warts associated with fingolimod therapy. RESULTS: Each of the five cases presenting with chronic warts while receiving fingolimod therapy had prolonged periods of lymphopenia and improvements were seen following dose reduction or cessation of fingolimod. CONCLUSION: Cutaneous warts are associated with human papilloma virus (HPV) infection, suggesting an increased risk of other HPV-driven conditions such as cervical cancer following fingolimod administration. HPV viruses are responsible for approximately 90% of cervical cancers as well as a significant portion of anogenital cancers and have a high prevalence in sexually active adults. Given the reduced immune response to viral infections and potential impaired cancer surveillance in those receiving fingolimod, HPV vaccination and frequent assessment for the development of HPV-associated malignancies are recommended.

Human papillomavirus infection in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice.

These guidelines from the American Society of Transplantation Infectious Diseases Community of Practice update the epidemiology and management of human papillomavirus (HPV) infections in organ transplant recipients. HPV is one of the most common sexually transmitted infections and is associated with cancers of the anogenital region. Increasing evidence suggests an association with head and neck cancers as well. Solid organ transplant recipients have a higher risk of HPV infection than the general population. Infection manifests as premalignant lesions, warts, or cancer of the cervix, penis, vulva, scrotum, and anal canal. Most are asymptomatic initially, so diagnosis can be difficult without screening. A vaccine is available though not effective in preventing all cancer-causing strains. Organ transplant recipients should be screened for HPV-associated cancers and appropriate therapy initiated in a timely manner. Further studies are warranted to delineate the most effective screening methods and therapeutic modalities, including whether changes in immunosuppression are effective in attenuating disease.

Correlation between cervical carcinogenesis and tobacco use by sexual partners.

PURPOSE: Investigating the effects of active smoking, passive smoking and semen of tobacco smoking sexual partners on the carcinogenesis of uterine cervix. INTRODUCTION: It is now well-established that persistence of Human Papillomavirus (HPV) infection is the strongest epidemiologic factor associated with intraepithelial neoplasia and cancer of cervix, as well as in other related locations such as in the vagina, vulva, anus, oral cavity, etc. A 1999 study indicates that the worldwide HPV prevalence in cervical carcinomas is 99,7 per cent. Multiple factors seem to intervene on cervical carcinogenesis, many of them related to tobacco, especially by direct local carcinogenic effect and local immunosuppression. Many studies have also shown that active or passive smoking in women (family-work environment, meeting places, etc.) greatly affects the occurrence, progression and degree of malignancy of carcinogenesis. Furthermore, particularly increased levels of nicotine and cotinine in the cervical mucus as well as prostate sperm fluids and urinary cotinine:creatinine ratios in smokers and passive smokers indicate that tobacco constituents do indeed reach the uterine cervix and lead to increased modification of DNA in cervical epithelium, suggesting biochemical evidence consistent with smoking as a cause of cervical cancer. The research presented today, though it took place over 30 decades ago (1975-1986 at the University Gynecological and Obstetric Clinic of Homburg ad Saar), we hope will serve as a reminder and contributing factor for further examination of the increased risk of cervical cancer in non-smoking women living with smoking partners. STUDY: The study analyzed a total of one thousand five-hundred and forty (1,540) medical history sheets (krankenblätter) of women aged from eighteen to seventy-four (18-74) years old that were admitted, treated, examined (PAP TEST) or referred for further tests by their family physicians to the Homburg ad Saar Clinic between 1975-1986. The study evaluated the general medical history of the 1,540 women with a special focus on gynecological and obstetric related data and gathered additional information from patients through written questionnaires completed via phone, mail or personal interviews. Among a range of factors and data studied during the research, our current presentation and discussion will focus on the development of cervical neoplasms in women, examining results from three different study groups: smokers, passive-smokers and women with smoking sexual partners. RESULTS: Five hundred and forty-four cases (544) out of the overall study sample of one thousand five-hundred and forty (1,540) women, were identified as cases with pathological cell abnormalities (35.32%). Following diagnosis and treatment of transient lesions due to various inflammations (vaginitis, cervicitis etc.) one hundred and twelve (112) cases (20.59%) showed varying degrees of mild/reversible up to CIN 1-3 intraepithelial lesions. From the above sample of one hundred and twelve 112 cases, nineteen cases (19) were smoke free women who never smoked themselves, were not exposed to passive smoking and had non-smoker partners (16.96%). Forty-four (44) cases (39.29%) were female smokers, twenty-two (22) cases (19.64%) were women exposed to regular passive smoking (family-work environment) with a smoke-free partner and twenty-seven (27) cases (24.11%) were women non-smokers with a smoker partner. From the above findings, intraepithelial lesions were found to be higher (and with a progressive malign ratio) on the study groups that were associated with tobacco use either active or passive and therefore, the synergistic harmful effect of smoking, progressively from passive smokers to active smokers, is clearly evident on the occurrence and progression of cervical malignancies. As already mentioned above, the presence of HPV has been widely proven to be almost exclusively the cause of different degrees of neoplasia in the cervix for more than 99.7% of cervical carcinogenesis. However, the harmful effects of a) active smoking, b) passive smoking and c) the exposure to tobacco constituents through an active smoker partner, in women, should be sought and possibly attributed to the catalytic reduction of cervical self-defense and overall cervical immunity disruption which results to the exposure of cervix to elevated levels of nicotine-cotinine and cancer-causing chemicals related to smoking, may work together with certain types of HPV limiting the natural ability of the cervix to defend against carcinogenesis and therefore increase the likelihood of developing cancer. CONCLUSION: Since the almost exclusively cause of cervical neoplasms is due to the presence and carcinogenic activity of HPV, the harmful/synergistic effect of smoking, passive smoking and partner smoking cannot be attributed to the direct carcinogenic effect of nicotine but to the overall damage of the immune system as we as the reduction of cervical self-defense making it more vulnerable to the carcinogenic nature of HPV, in particular the increased pathogenic types 16 and 18. Lastly, another potential correlation that could be further examined is the potential effects of tobacco constituents in cervical fluids on the self-defense system of the male reproductive system.

Folate Deficiency Facilitates Genomic Integration of Human Papillomavirus Type 16 DNA In Vivo in a Novel Mouse Model for Rapid Oncogenic Transformation of Human Keratinocytes.

Background: Epidemiologic and in vitro studies suggest independent linkages between poor folate and/or vitamin B-12 nutrition, genomic human papillomavirus (HPV) type 16 viral integration, and cancer. However, there is no direct evidence in vivo to support the causative role of poor folate nutrition in HPV16 integration into the cellular genome. Objective: We tested the hypothesis that folate deficiency enables the integration of HPV16 into the genome of HPV16-harboring keratinocytes, and could thereby influence earlier transformation of these cells to cancer in an animal model. Methods: HPV16-harboring human keratinocytes [(HPV16)BC-1-Ep/SL] were differentiated into 3-dimensional HPV16-organotypic rafts under either folate-replete or folate-deficient conditions in vitro. These were then subcutaneously implanted in severely immunocompromised female Beige Nude XID (Hsd: NIHS-LystbgFoxn1nuBtkxid) mice (4-6 wk old, 16-18 g) fed either a folate-replete diet (1200 nmol folate/kg diet) or a progressively folate-deficient diet (600 or 400 nmol folate/kg diet) for 2 mo prior to raft-implantation surgery, and indefinitely thereafter. The tumors that subsequently developed were characterized for onset, pattern of growth, morphology, HPV16 oncogene expression, and HPV16-genomic integration. Results: All HPV16-organotypic rafts developed in either folate-replete or physiologic low-folate media in vitro and subsequently implanted in folate-replete mice eventually transformed into aggressive malignancies within weeks. When compared to HPV16-high folate-organotypic raft-derived tumors from mice fed either a 1200 or 600 nmol folate/kg diet, those raft-derived cancers that developed in mice fed a 400 nmol folate/kg diet expressed significantly more HPV16 E6 (1.8-fold more) and E7 (2.8-fold more) oncogenic proteins (P = 0.001), and revealed significantly more HPV16-integration sites in genomic DNA (2-fold more), either directly into, or in the vicinity of, cellular genes (P < 0.05). Conclusions: This unprecedented animal model for the consistent rapid transformation of differentiated (HPV16)BC-1-Ep/SL-derived organotypic raft-keratinocytes to cancer in Beige Nude XID mice confirms that dietary folate deficiency can profoundly influence and modulate events leading to HPV16-induced carcinogenesis, and facilitates genomic integration of HPV16 DNA in vivo.

Importance of High-Risk Human Papillomavirus Infection Detection in Female Renal Transplant Recipients in the First Year after Transplantation.

Objectives: Most of human papillomavirus (HPV) infections are "cleared" by the immune system; however, in cases of immune system suppression, infections could lead to development of malignancies. The aim of this study was to find out the frequency of HR-HPV infection in early period after renal transplantation in recipients receiving immunosuppressive therapy and to follow the progression of the infection up to one year. Methods: 43 female renal transplant recipients and 79 healthy female individuals as a control group were enrolled in this investigation. For the detection of HPV infection, patients' samples (blood and vaginal swabs) were collected two weeks after transplantation with following collection of six months and one year. Different polymerase chain reactions for HR-HPV genomic sequences detection and ELISA kit for detection of anti-HPV IgG antibodies were used. Results: In this study, we show that frequency rate of HR-HPV infection has increased in the first year after transplantation from early stage of immunosuppressive therapy (from 24% to 36%). Also an increase of HR-HPV load was detected over time, showing the highest median viral load at sixth month after transplantation. Conclusions: From the obtained data, it follows that it is very important to carefully monitor patients receiving immunosuppression therapy on progression of HR-HPV.

Cigarette Smoking Promotes Infection of Cervical Cells by High-Risk Human Papillomaviruses, but not Subsequent E7 Oncoprotein Expression.

Persistent cervical infection with high-risk human papillomaviruses (hrHPVs) is a necessary, but not sufficient, condition for the development of cervical cancer. Therefore, there are other co-factors facilitating the hrHPV carcinogenic process, one of which is smoking. To assess the effect of smoking on high-risk (hr) HPV DNA positivity and on the expression of HPV E7 oncoprotein, as a surrogate of persistent hrHPV infection, we used data from women recruited for the PIPAVIR project, which examined the role of E7 protein detection in cervical cancer screening. Women were tested for hrHPV DNA, using Multiplex Genotyping (MPG), and E7 protein, using a novel sandwich ELISA method, and gave information on their smoking habits. Among 1473 women, hrHPV prevalence was 19.1%. The odds ratio (OR) for hrHPV positivity of smokers compared to non-smokers was 1.785 (95% confidence intervals (CI): 1.365-2.332, p < 0.001). The ORs for E7 positivity, concerning hrHPV positive women, ranged from 0.720 to 1.360 depending on the E7 detection assay used, but this was not statistically significant. Smoking increases the probability of hrHPV infection, and smoking intensity is positively associated to this increase. Smoking is not related to an increased probability of E7 protein positivity for hrHPV positive women.

[The relationship between cervicovaginal and oral HPV infection]. / Vztah mezi cervikovaginální a orální HPV infekcí.

OBJECTIVE: To summarize current knowledge of the relationship of genital and oral HPV infection in women. DESIGN: Review article. SETTING: Gynecologic Oncology Center, Department of Gynecology and Obstetrics, Hospital Na Bulovce and 1st Medical School of Charles University, Prague; Gynecologic Oncology Center, Department of Gynecology and Obstetrics, General Faculty Hospital and 1st Medical School of Charles University, Prague; ENT Department, Hospital Na Bulovce, Prague. METHODS AND RESULTS: The infection of human papillomavirus (HPV) is strongly associated with the development of anogenital cancers and of a subset of head and neck squamous cell cancers, yet a quite little is known about the interrelationship between oral and cervicovaginal HPV infections. A key issue in oral HPV infection is whether it can be brought about a genital HPV infection, through sexual or other contact and by autoinoculation, or whether it can be considered a fully independent event. Pertinent to this issue is the frequency of oral HPV infection in women with a cervical HPV infection. Some studies show that females with genital HPV infection are at higher risk for oral infection and HPV genotype-concordance with genital infection are more prevalent than could be expected by chance. However, more data are needed to better understand the natural history of HPV infection at each anatomic site. CONCLUSION: The relationship of oral to cervicovaginal HPV infection remains unclear. Nevertheless, published data suggest that HPV infections at these two sites are not entirely independent, although genotype-specific concordance is low.

Country-specific HPV-related genital disease among men residing in Brazil, Mexico and The United States: The HIM study.

The purpose of this study was to assess whether the incidence of histopathologically confirmed condyloma and penile intraepithelial neoplasia (PeIN) and rates of genital HPV infection progression to these lesions differs by country (Brazil, Mexico and the U.S.). At each visit, lesions were biopsied and were categorized by pathologic diagnoses. The Linear Array genotyping method was used to identify HPV genotypes from genital swabs, while the INNO-LiPA HPV Genotyping Extra method was used for tissue specimens. Age-specific analyses were conducted for lesion incidence by country, with Kaplan-Meier estimation of cumulative incidence. The proportion of HPV infections that progressed to condyloma and PeIN, the median time to lesion development and the incidence rates were estimated by country. When comparing demographic and sexual characteristics across the three countries, sexual orientation (p = 0.008) and lifetime number of female sexual partners (p < 0.0001) were differentially associated with lesion incidence in the three countries. Condyloma incidence in Brazil and the U.S. decreased with age, while incidence remained constant across the lifespan in Mexico. There were no differences by country and age for PeIN incidence. HPV types 6 and 11 were the most common types to progress to condyloma and HPV types 16, 6 and 11 were the most common types to progress to PeIN in all three countries. The continuous risk of condyloma and PeIN across all age groups and countries in this study emphasizes the need to ensure that strong HPV immunity, such as that obtained through vaccination, is maintained across the lifespan of men.

O-linked-N-acetylglucosamine transferase is associated with metastatic spread of human papillomavirus E6 and E7 oncoproteins to the lungs of mice.

High-risk human papilloma virus (HPV) 16/18 infections are often found in lung cancer. The cellular mechanisms involved in the metastatic spread of HPV-infected cervical cancer cells remain largely elusive. High O-linked-N-acetylglucosamine (O-GlcNAc) modification has also been observed in lung cancer. In the present study, we assessed the relationship between O-GlcNAc transferase (OGT) and HPV 16/18 E6/E7, or C-X-C chemokine receptor type 4 (CXCR4), in HeLa cells and in lungs of xenografted mice. Depleting OGT with an OGT-specific shRNA significantly decreased levels of E6 and E7 oncoproteins in HeLa cells and xenograft tumors, and reduced tumor formation in vivo. Western blotting and immunofluorescence analysis showed significantly decreased expression levels of E6, E7, and HCF-1 in the lungs of xenografted mice treated with an OGT-specific shRNA compared to those treated with non-targeting shRNA. Additionally, levels of E7 or OGT co-localized with Ki-67 were significantly decreased in the lungs of xenografted mice treated with OGT-specific shRNA compared to those treated with non-targeting shRNA. Moreover, levels of CXCR4 were significantly decreased in HeLa cells and in the lungs of xenografted mice treated with OGT-specific shRNA compared to those treated with non-targeting shRNA; this may be related to reduced adhesion or invasion of circulating HPV-positive tumor cells. These findings provide novel evidence that OGT functions in metastatic spread of HPV E6/E7-positive tumor cells to the lungs through E6/E7, HCF-1 and CXCR4, suggesting OGT might be a therapeutic target for HPV-positive lung cancer.