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Human Papillomaviruses have co-evolved with their human host, with each of the over 200 known HPV types infecting distinct epithelial niches to cause diverse disease pathologies. Despite the success of prophylactic vaccines in preventing high-risk HPV infection, the development of HPV anti-viral therapies has been hampered by the lack of enzymatic viral functions, and by difficulties in translating the results of in vitro experiments into clinically useful treatment regimes. In this review, we discuss recent advances in anti-HPV drug development, and highlight the importance of understanding persistent HPV infections for future anti-viral design. In the infected epithelial basal layer, HPV genomes are maintained at a very low copy number, with only limited viral gene expression; factors which allow them to hide from the host immune system. However, HPV gene expression confers an elevated proliferative potential, a delayed commitment to differentiation, and preferential persistence of the infected cell in the epithelial basal layer, when compared to their uninfected neighbours. To a large extent, this is driven by the viral E6 protein, which functions in the HPV life cycle as a modulator of epithelial homeostasis. By targeting HPV gene products involved in the maintenance of the viral reservoir, there appears to be new opportunities for the control or elimination of chronic HPV infections.

Human papillomaviruses (HPV) are non-enveloped DNA viruses infecting cutaneous and mucosal squamous epithelia. Sexually transmitted HPV-types that are carcinogenic to humans such as HPV16 can induce cervical and other anogenital cancers. Virus transmission through fomites such as inadequately disinfected gynecological equipment is a further potential transmission route. Since HPV cannot be easily grown in cell culture, polyomavirus SV40 has been used as a surrogate virus when testing the virucidal activity of chemical disinfectants. So far, studies that have compared the virucidal activity of different disinfectants against HPV and SV40 are lacking. Here, we evaluated the susceptibility of HPV16 pseudovirus and SV40 to seven active biocidal substances using quantitative suspension tests. Ethanol, glutaraldehyde (GTA), dodecyldipropylentriamin (DPTA), and ortho-phthalaldehydes (OPA) were able to reduce the infectivity of HPV16 pseudovirus >99.99% after 5 min. In contrast, isopropanol, peracetic acid (PAA), and quaternary ammonium compounds with alkylamines (QAC) only led to a slight or no reduction in infectivity. Concerning SV40, only GTA (60 min contact time), PAA, and OPA had virus-inactivating effects. In conclusion, the virucidal activity of three out of seven disinfectants tested was different for HPV16 pseudovirus and SV40. In this study, SV40 was shown to be a reliable surrogate virus for HPV when testing isopropanol-, GTA-, QAC-, and OPA-based disinfectants.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been used as antiviral agents for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. We performed a systematic review to examine whether prior clinical studies that compared the effects of CQ and HCQ to a control for the treatment of non-SARS-CoV2 infection supported the use of these agents in the present SARS-CoV2 outbreak. PubMed, EMBASE, Scopus and Web of Science (PROSPERO CRD42020183429) were searched from inception through 2 April 2020 without language restrictions. Of 1766 retrieved reports, 18 studies met our inclusion criteria, including 17 prospective controlled studies and one retrospective study. CQ or HCQ were compared to control for the treatment of infectious mononucleosis (EBV, n = 4), warts (human papillomavirus, n = 2), chronic HIV infection (n = 6), acute chikungunya infection (n = 1), acute dengue virus infection (n = 2), chronic HCV (n = 2), and as preventive measures for influenza infection (n = 1). Survival was not evaluated in any study. For HIV, the virus that was most investigated, while two early studies suggested HCQ reduced viral levels, four subsequent ones did not, and in two of these CQ or HCQ increased viral levels and reduced CD4 counts. Overall, three studies concluded CQ or HCQ were effective; four concluded further research was needed to assess the treatments' effectiveness; and 11 concluded that treatment was ineffective or potentially harmful. Prior controlled clinical trials with CQ and HCQ for non-SARS-CoV2 viral infections do not support these agents' use for the SARS-CoV2 outbreak., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA.)

In 2020, the World Health Organisation (WHO) published a strategy to eliminate cervical cancer as a public health concern. In South Africa, despite having a national screening policy in place since 2000, diagnosed cervical cancer incidence has shown no signs of decline. We extend a previously developed individual-based model for human immunodeficiency virus (HIV) and human papillomavirus (HPV) infection to include progression to cervical cancer. The model accounts for future reductions in HIV incidence and prevalence and includes a detailed cervical cancer screening algorithm, based on individual-level data from the public health sector. We estimate the impact of the current prevention programme and alternative screening scenarios on cervical cancer incidence. The South African screening programme prevented 8600 (95%CI 4700-12 300) cervical cancer cases between 2000 and 2019. At current levels of prevention (status quo vaccination, screening, and treatment), age-standardised cervical cancer incidence will reduce from 49.4 per 100 000 women (95%CI 36.6-67.2) in 2020, to 12.0 per 100 000 women (95%CI 8.0-17.2) in 2120. Reaching WHO's prevention targets by 2030 could help South Africa reach elimination (at the 10/100 000 threshold) by 2077 (94% probability of elimination by 2120). Using new screening technologies could reduce incidence to 4.7 per 100 000 women (95%CI 2.8-6.7) in 2120 (44% probability of elimination at the 4/100 000 threshold). HPV vaccination and decreasing HIV prevalence will substantially reduce cervical cancer incidence in the long term, but improvements to South Africa's current screening strategy will be required to prevent cases in the short term. Switching to new screening technologies will have the greatest impact., (© 2021 UICC.)

Over the recent few years rutin has gained wider attention in exhibiting inhibitory potential against several oncotargets for inducing apoptotic and antiproliferative activity in several human cancer cells. Several deregulated signaling pathways are implicated in cancer pathogenesis. Therefore we have inclined our research towards exploring the anticancerous efficacy of a very potent phytocompound for modulating the incontinent expression of these two crucial E6 and E7 oncogenes. Further, inhibitory efficacy of rutin against human papillomavirus (HPV)-E6 and E7 oncoproteins in cervical cancer has not been elucidated yet. This research addresses the growth inhibitory efficacy of rutin against E6 and E7 oncoproteins in HeLa cells, which is known to inactivate several tumor suppressor proteins such as p53 and pRB. Rutin treatment exhibited reduced cell viability with increased cell accumulation in G0/G1 phase of cell cycle in HeLa cell lines. Additionally, rutin treatment has also led to down-regulation of E6 and E7 expression associated with an increased expression of p53 and pRB levels. This has further resulted in enhanced Bax expression and decreased Bcl-2 expression releasing cytochrome c into cytosol followed by caspase cascade activation with cleavage of caspase-3, caspase-8 and caspase-9. Further, in silico studies have also supported our in vitro findings by exhibiting significant binding energy against selected target oncoproteins. Therefore, our research findings might recommend rutin as one of the potent drug candidate in cervical cancer management via targeting two crucial oncoproteins associated with viral progression., (© 2021 The Author(s).)

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.

Background: Recent publications from a single research group have suggested that aldehyde-based high-level disinfectants (HLDs), such as ortho-phthalaldehyde (OPA), are not effective at inactivating HPVs and that therefore, patients may be at risk of HPV infection from medical devices. These results could have significant public health consequences and therefore necessitated evaluation of their reproducibility and clinical relevance., Methods: We developed methods and used standardised controls to: (1) quantify the infectious levels of clinically-sourced HPVs from patient lesions and compare them to laboratory-derived HPVs, (2) evaluate experimental factors that should be controlled to ensure consistent and reproducible infectivity measurements of different HPV genotypes, and (3) determine the efficacy of select HLDs., Findings: A novel focus forming unit (FFU) infectivity assay demonstrated that exfoliates from patient anogenital lesions and respiratory papillomas yielded infectious HPV burdens up to 2.7 × 10 3 FFU; therefore, using 2.2 × 10 2 to 1.0 × 10 4 FFU of laboratory-derived HPVs in disinfection assays provides a relevant range for clinical exposures. RNase and neutralising antibody sensitivities were used to ensure valid infectivity measures of tissue-derived and recombinant HPV preparations. HPV infectivity was demonstrated over a dynamic range of 4-5 log 10 ; and disinfection with OPA and hypochlorite was achieved over 3 to >4 log 10 with multiple genotypes of tissue-derived and recombinant HPV isolates., Interpretation: This work, along with a companion publication from an independent lab in this issue, address a major public health question by showing that HPVs are susceptible to HLDs., Funding: Advanced Sterilization Products; US NIH (R01CA207368, U19AI084081, P30CA118100)., Competing Interests: Declaration of Competing Interest M.A.O. reports grants, personal fees, and non-financial support from Advanced Sterilization Products, grants from U.S. National Institutes of Health, during the conduct of the study; A.G.W. reports personal fees and non-financial support from ASCCP, non-financial support from ACOG, non-financial support from Loktal Medical Electronics, personal fees and non-financial support from CSCCP (Chinese Society for colposcopy and cervical pathology, personal fees and non-financial support from Henan People's Regional Hospital, personal fees from Southcentral Foundation (Alaska Native Corp), non-financial support from FECOLSOG (Colombian colposcopy society), non-financial support from COMEGIC (Mexican colposcopy society), non-financial support from Doctors Hospital at Renaissance, non-financial support from MD Anderson, non-financial support from Univ Texas Rio Grande Valley, non-financial support from Global Coalition against Cervical Cancer, non-financial support from AIDS Malignancy Consortium, personal fees and non-financial support from Deaconess Beth Israel Hospital, personal fees and non-financial support from Texas Tech University, personal fees and non-financial support from ABPTGIC (Brazilian colposcopy society), outside the submitted work. V.B., N.A.P, R.T.S., E.C.B. and R.M. have nothing to disclose. A.S., J.Y. and M.R. are employees of Advanced Sterilization Products. G.E. is an employee and shareholder of Johnson & Johnson, which was the parent company for Advanced Sterilization Products and Janssen Pharmaceutica NV at the time the research was conducted., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Cervical cancer remains a global health burden despite the introduction of highly effective vaccines for the prophylaxis of causative human papillomavirus infection (HPV). Current efforts to eradicate cervical cancer focus on the development of broadly protective, cost-effective approaches. HPV minor capsid protein L2 is being recognized as a promising alternative to the major capsid protein L1 because of its ability to induce responses against a wider range of different HPV types. However, a major limitation of L2 as a source of cross-neutralizing epitopes is its lower immunogenicity compared to L1 when assembled into VLPs. Various approaches have been proposed to overcome this limitation, we developed and tested ferritin-based bio-nanoparticles displaying tandemly repeated L2 epitopes from eight different HPV types grafted onto the surface of Pyrococcus furiosus thioredoxin (Pf Trx). Genetic fusion of the Pf Trx-L2(8x) module to P. furiosus ferritin (Pf Fe) did not interfere with ferritin self-assembly into an octahedral structure composed by 24 protomers. In guinea pigs and mice, the ferritin super-scaffolded, L2 antigen induced a broadly neutralizing antibody response covering 14 oncogenic and two non-oncogenic HPV types. Immune-responsiveness lasted for at least one year and the resulting antibodies also conferred protection in a cervico-vaginal mouse model of HPV infection. Given the broad organism distribution of thioredoxin and ferritin, we also verified the lack of cross-reactivity of the antibodies elicited against the scaffolds with human thioredoxin or ferritin. Altogether, the results of this study point to P. furiosus ferritin nanoparticles as a robust platform for the construction of peptide-epitope-based HPV vaccines., Competing Interests: At the time the research described in this manuscript was performed, FY, FM, XZ, and MM were employees of DKFZ, while GS and SO were employees of University of Parma., (Copyright © 2020 Yang, Mariz, Zhao, Spagnoli, Ottonello and Müller.)

Persistent infection with high-risk human papillomavirus (hrHPV) genotypes results in a large number of anogenital and head and neck cancers worldwide. Although prophylactic vaccination coverage has improved, there remains a need to develop methods that inhibit viral transmission toward preventing the spread of HPV-driven disease. Defensins are a class of innate immune effector peptides that function to protect hosts from infection by pathogens such as viruses and bacteria. Previous work utilizing α and β defensins from humans has demonstrated that the α-defensin HD5 is effective at inhibiting the most common high-risk genotype, HPV16. A third class of defensin that has yet to be explored are θ-defensins: small, 18-amino acid cyclic peptides found in old-world monkeys whose unique structure makes them both highly cationic and resistant to degradation. Here we show that the prototype θ-defensin, rhesus theta defensin 1, inhibits hrHPV infection through a mechanism involving capsid clustering that inhibits virions from binding to cell surface receptor complexes., (Copyright © 2020 Skeate, Segerink, Garcia, Fernandez, Prins, Lühen, Voss, Da Silva and Kast.)

Introduction : Human papillomaviruses (HPVs) are common sexually transmitted pathogens, causally associated with cervical cancer and other anogenital cancers, as well as approximately 20% of head and neck cancers. The HPV vaccine is an exceptional primary prevention tool, but the question of adequate secondary-prevention strategies remains open. The aim of this review is to better clarify the role of carrageenan in HPV prevention-strategies. Areas covered : A comprehensive literature search was performed (PubMed/MEDLINE, Embase, Google Scholar, Cochrane Databases) to identify articles on the use of carrageenan against HPV infection. The studies were identified using combinations of the search terms 'carrageenan,' 'papillomavirus,' 'HPV,' including only English language papers. Expert opinion : Our review data confirmed the 'inhibitory role' of carrageenan against HPV- pseudoviruses infection on different cell types. The most accredited mechanism to explain this effect involves the direct binding of CG to the viral capsid creating a 'physical' obstacle. However, a different susceptibility to carrageenan for different HPV types has been highlighted, suggesting the possibility of other strategies to infect the host. There are also relevant emerging data regarding the possible role of carrageenan as an adjuvant for antigen-specific immune responses and antitumor effects.

Objective: Human PapillomaVirus (HPV) vaccination has been introduced in recent years in clinical practice as the most effective primary prevention strategy for cervical cancer and HPV-induced lesions, either pre-malignant or benign. Since its introduction, HPV vaccination has been progressively demonstrated as extremely effective in preventing extra-genital and male diseases also; furthermore, non only adolescents but adult subjects have been investigated and reported as positively responding to vaccine immunostimulation. More recently, effectiveness of post-treatment vaccine administration has been preliminarily investigated with very promising results in terms of decreased recurrences. On this basis, we report an Italian-focused picture of the state of the art and take a position in favour of the extension of HPV vaccination to male adolescents, to older age groups and to already treated subjects.

Sexual transmission is the most common pathway for the spread of Human papillomavirus (HPV). However, the potential for iatrogenic HPV infections is also real. Even though cleared by the Food and Drug Administration and recommended by the World Federation for Ultrasound in Medicine and Biology, several disinfectants including glutaraldehyde and o-phthalaldehyde have shown a lack of efficacy for inactivating HPV. Other methods such as ultraviolet C and concentrated hydrogen peroxide have been shown highly effective at inactivating infectious HPV. In this study, two chlorine dioxide systems are also shown to be highly efficacious at inactivating HPV. An important difference in these present studies is that as opposed to testing in suspension or using a carrier, we dried the infectious virus directly onto endocavitary ultrasound probes and nasendoscopes, therefore, validating a more realistic system to demonstrate disinfectant efficacy., (© 2020 Wiley Periodicals, Inc.)

Background: Human papillomavirus (HPV) is largely vaccine preventable. The Healthy People 2020 target goal for vaccine administration is 80%. Current United States (U. S.) rates are far lower primarily because of vaccine hesitancy and lack of provider recommendation., Objective: Implement a risk reduction initiative to increase HPV vaccine rates in females aged 12-26 in five rural counties in Maryland., Methods: A convenience sample from a rural community screened an HPV documentary movie, Questionnaire responses pre- and postscreening were surveyed for impact on vaccine readiness. Postscreening focus group comments were analyzed for common themes. Females aged 12-26 from a University Medical Group Women's Health Center located in rural Maryland were targeted. Chart review of immunization records 90 days pre- and postprovider vaccine recommendation demonstrated impact., Results: Public awareness events have the potential to impact HPV vaccine hesitancy, but this research did not achieve statistical significance. Direct provider to patient recommendations resulted in a 15% increase in HPV immunizations., Conclusions: Education of vaccine-eligible individuals should be undertaken., Implications for Nursing: Providers who recommend administration of the vaccine significantly increase immunization rates., (© Copyright 2020 Springer Publishing Company, LLC.)

Most cell-based and animal experiments have shown that green tea catechins (GTC) exhibit various health benefits. In human experimental and epidemiological studies, there are conflicting results, and more precise investigations are required. One of the most effective ways to prove beneficial health effects in humans might be clinical intervention studies. Polyphenon ® E was developed as a standardized GTC preparation, which was approved by Food and Drug Administration of US in 2006 as a medication to treat genital warts (Veregen ® or sinecatechins). Positive efficacy of Polyphenon ® E/sinecatechins/Veregen ® (PSV) on anogenital warts has been demonstrated in several epidemiological studies and there have been several case reports to show the clinical effectiveness of PSV. In addition, several studies have provided evidence to suggest that PSV is effective in other human papillomavirus (HPV)-related diseases, although some studies failed to show such effects. Since (-)-epigallocatechin gallate (EGCG) is the major component of PSV, the mechanism of the action of PSV might be deduced from that of EGCG. The microarray analysis of the biopsy samples from the patients suggested that apoptosis induction and the downregulation of inflammation are involved in the mechanism of the action of PSV in the clearance of anogenital warts. Cell-based and animal experiments using PSV also demonstrated effects similar to those elicited by EGCG, explaining how PSV works to induce apoptosis and exert anti-inflammatory actions in HPV-related diseases. Future studies would clarify what kinds of diseases respond effectively to PSV, showing health benefits of GTC and EGCG in humans.

The oropharynx has become the leading primary site for Human Papilloma Virus (HPV)-associated head and neck cancer. HPV positive oropharyngeal squamous cell carcinoma (HPV+ OSCC) has emerged as an epidemic not easily recognized by many physicians, resulting in delays in diagnosis and management. HPV+ OSCC traditionally refers to younger, healthier patients with high economic status and high-risk sexual behavior and is related to improved prognosis. De-intensification strategies are being evaluated in ongoing clinical trials and if validated, might help spare severe morbidity associated with current cisplatin-based chemoradiotherapy, which is the standard of care for all patients with locally advanced head and neck cancer. On the other hand, whether HPV status represents an important prognostic factor for non-oropharyngeal sites remains to be elucidated.

Dental professionals are encouraged by the American Dental Association (ADA) to recommend the HPV vaccine to eligible patients. To better understand their comfort level in following this recommendation, we conducted a mixed methods study of dentists and dental hygienists. A total of 173 providers were surveyed and 8 interviewed. The majority felt they had an important role in preventing HPV-related OPC and that they should educate their patients and encourage HPV vaccination. However, most providers had low knowledge about HPV and expressed a need to obtain more information on the topic. In particular, they desired information about the HPV vaccine, its connection to cancer and where to refer patients for vaccination. They also wanted access to visual aids to help them bring up the topic. This study demonstrates the need to develop and disseminate educational programs for dental providers so they can assist with efforts to raise HPV vaccination rates., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Evidence of the safety and protective benefits of human papillomavirus virus (HPV) vaccines as an anti-cancer measure is overwhelming. However, vaccine uptake varies widely across countries and falls short of levels needed to achieve population immunity. We highlight policy measures that would help ensure greater worldwide coverage and save lives., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Women globally need access to multipurpose prevention technologies (MPTs) that prevent human immunodeficiency virus (HIV), sexually transmitted infections that increase HIV acquisition/transmission risk, and unintended pregnancy. Seeking an MPT with activity against HIV, herpes simplex virus-2 (HSV-2), and human papillomavirus (HPV), we developed a prototype intravaginal ring (IVR), the MZCL IVR, which released the antiviral agents MIV-150, zinc acetate, and carrageenan (MZC for short) and the contraceptive levonorgestrel (LNG). Previously, we showed that an MZC gel has potent activity against immunodeficiency viruses, HSV-2, and HPV and that the MZCL (MZC with LNG) IVR releases all four components in macaques in vivo at levels associated with efficacy. Vaginal fluid from treated macaques has in vitro activity against HIV, HSV-2, and HPV. Herein, we assessed the ability of the MZCL IVR to protect macaques against repeated co-challenge with HSV-2 and SHIV-RT (simian immunodeficiency virus [SIV] containing the reverse transcriptase gene from HIV) and prevent hormonal cycling. We evaluated in vivo drug release in co-challenged macaques by measuring drug levels in blood and vaginal fluid and residual drug levels in used IVRs. The MZCL IVR significantly prevented SHIV-RT infection, reduced HSV-2 vaginal shedding, and prevented cycling. No non-nucleoside HIV reverse transcriptase inhibitor (NNRTI)-resistant SHIV was detected in macaques that became infected after continuous exposure to MZC from the IVR. Macaques wearing the MZCL IVR also had carrageenan levels in vaginal fluid expected to protect from HPV (extrapolated from mice) and LNG levels in blood associated with contraceptive efficacy. The MZCL IVR is a promising MPT candidate that warrants further development.

Condylomata acuminata are benign proliferations of skin and mucosa caused by the human papilloma virus infection (hereinafter referredto as HPV). It is one of the most common sexually transmitted diseases in the world, whose incidence rate has increased in the last three decades. Current treatment involves the physical destruction of the infected cells. The fact that there are many different types of treatment goes to show that none of them are uniformly effective or directly antiviral.

Cervical cancer is the third most common cancer among women worldwide and is responsible for 275.000 deaths each year. The development of cervical cancer has been linked to cell cycle disturbances caused by persistent expression of high- risk HPV oncoproteins (E5, E6 and E7), which modulate the expression of host genes and cellular microRNAs. An estimated 5 million women throughout the world are currently infected by HPV and several of them will develop invasive cervical cancer. Despite failures in conventional screening tests, approved therapies have no direct effect on HPV infection. In view of this, effective therapy for cervical cancer is still urgently needed, particularly in developing countries where more than 85% of fatal cases occur. In this paper we review the current molecular targeted therapies which are being explored and may have a significant impact on the treatment of HPV- related cervical dysplasia and carcinoma.

Cervical cancer is the sixth most common cancer in women worldwide and the leading cause of women's death in developing countries. Nearly all cervical cancers are associated with infection of the human papillomavirus (HPV). This sexually transmitted pathogen disrupts the cell cycle via two oncoproteins: E6 and E7. Cells respond to E7-mediated degradation of pRB by upregulating the p53 tumor suppressor pathway. However, E6 thwarts this response by binding to the cellular E6-Associating Protein (E6AP) and targeting p53 for degradation. These two virus-facilitated processes pave the way for cellular transformation. Prophylactic HPV vaccines are available, but individuals already infected with HPV lack drug-based therapeutic options. To fill this void, we sought to identify small molecule inhibitors of the E6-E6AP interaction. We designed an ELISA-based high throughput assay to rapidly screen compound libraries, and hits were confirmed in several orthogonal biochemical and cell-based assays. Over 88,000 compounds were screened; 30 had in vitro potencies in the mid-nanomolar to mid-micromolar range and were classified as validated hits. Seven of these hits inhibited p53 degradation in cell lines with HPV-integrated genomes. Two compounds of similar scaffold successfully blocked p53 degradation and inhibited cell proliferation in cells stably transfected with E6. Together, these studies suggest that small molecules can successfully block E6-dependent p53 degradation and restore p53 activity. The compounds identified here constitute attractive starting points for further medicinal chemistry efforts and development into beneficial therapeutics.

Quadrivalent human papillomavirus (HPV) [types 6, 11, 16, 18] recombinant vaccine (Gardasil(®); Silgard(®)) is composed of virus-like particles formed by self-assembly of recombinant L1 capsid protein from each of HPV types 6, 11, 16 and 18. It is indicated for use from the age of 9 years as a two- or three-dose vaccination course over 6 months for the prevention of premalignant anogenital lesions, cervical and anal cancers, and genital warts caused by the vaccine HPV types. In placebo-controlled trials, quadrivalent HPV vaccine provided high-level protection against infection or disease caused by the vaccine HPV types over 2-4 years in females aged 15-45 years who were negative for the vaccine HPV types, and provided a degree of cross-protection against certain non-vaccine HPV types. The vaccine also provided high-level protection against persistent infection, anogenital precancerous lesions and genital warts caused by the vaccine HPV types over 3 years in susceptible males aged 16-26 years. Protection has been demonstrated for up to 8 years. In subjects who were negative for the vaccine HPV types, high seroconversion rates and high levels of anti-HPV antibodies were observed in females of all age ranges from 9 to 45 years and in males aged 9-26 years. The vaccine was generally well tolerated and was usually predicted to be cost effective in girls and young women. Therefore, quadrivalent HPV vaccine offers an effective means to substantially reduce the burden of HPV-related anogenital disease in females and males, particularly cervical cancer and genital warts.

Several viruses, including human papillomaviruses, depend on endosomal acidification for successful infection. Hence, the multisubunit enzyme vacuolar ATPase (V-ATPase), which is mainly responsible for endosome acidification in the cell, represents an attractive target for antiviral strategies. In the present study, we show that V-ATPase is required for human papillomavirus (HPV) infection and that uncoating/disassembly but not endocytosis is affected by V-ATPase inhibition. The infection inhibitory potencies of saliphenylhalamide, a proven V-ATPase inhibitor, and its derivatives, as well as those of other V-ATPase inhibitors, were analyzed on different HPV types in relevant cell lines. Variation in the selectivity indices among V-ATPase inhibitors was high, while variation for the same inhibitor against different HPV subtypes was low, indicating that broad-spectrum anti-HPV activity can be provided.

Prevalent infection with human herpes simplex 2 (HSV-2) or human papillomavirus (HPV) is associated with increased human immunodeficiency virus (HIV) acquisition. Microbicides that target HIV as well as these sexually transmitted infections (STIs) may more effectively limit HIV incidence. Previously, we showed that a microbicide gel (MZC) containing MIV-150, zinc acetate (ZA) and carrageenan (CG) protected macaques against simian-human immunodeficiency virus (SHIV-RT) infection and that a ZC gel protected mice against HSV-2 infection. Here we evaluated a modified MZC gel (containing different buffers, co-solvents, and preservatives suitable for clinical testing) against both vaginal and rectal challenge of animals with SHIV-RT, HSV-2 or HPV. MZC was stable and safe in vitro (cell viability and monolayer integrity) and in vivo (histology). MZC protected macaques against vaginal (p<0.0001) SHIV-RT infection when applied up to 8 hours (h) prior to challenge. When used close to the time of challenge, MZC prevented rectal SHIV-RT infection of macaques similar to the CG control. MZC significantly reduced vaginal (p<0.0001) and anorectal (p = 0.0187) infection of mice when 10(6) pfu HSV-2 were applied immediately after vaginal challenge and also when 5×10(3) pfu were applied between 8 h before and 4 h after vaginal challenge (p<0.0248). Protection of mice against 8×10(6) HPV16 pseudovirus particles (HPV16 PsV) was significant for MZC applied up to 24 h before and 2 h after vaginal challenge (p<0.0001) and also if applied 2 h before or after anorectal challenge (p<0.0006). MZC provides a durable window of protection against vaginal infection with these three viruses and, against HSV-2 and HPV making it an excellent candidate microbicide for clinical use.

Individuals infected with human immunodeficiency virus (HIV) have excess risk of developing human papillomavirus (HPV)-related disease. A substantial fraction of HPV-associated cancers is caused by HPV serotypes not included in the currently available vaccines. Among healthy women, both Cervarix(®) (HPV-16/18, GlaxoSmithKline Biologicals, GSK) and Gardasil(®) (HPV-6/11/16/18, Merck) have demonstrated partial cross-protection against certain oncogenic non-vaccine HPV-types. Currently, there are no available data on vaccine-induced cross-protection in men and little is known about cross-reactive immunity after HPV-vaccination of HIV-infected individuals. In an investigator-initiated trial, we randomized 91 HIV-positive men and women to receive vaccination with Cervarix(®) or Gardasil(®). The HPV-DNA status of the participants was determined with pcr before and after immunization. Cross-reactive antibody responses against HPV-31, HPV-33, and HPV-45 were evaluated for up to 12 months using a pseudovirion-based neutralization assay (PBNA). Geometric mean antibody titers (GMTs) were compared among vaccine groups and genders at 7 and 12 months.: Both vaccines induced anti-HPV-31, -33, and -45 neutralizing antibodies in participants who were seronegative and HPV-DNA negative for those types at study entry. Geometric mean antibody titers were comparable between vaccine groups. Interestingly, anti-HPV-31 and -33 antibody titers were higher among women compared with men at 7 and 12 months.: In conclusion, both licensed HPV-vaccines induced cross-neutralizing antibodies against frequent oncogenic non-vaccine serotypes HPV-31, HPV-33, and HPV-45 in HIV-infected adults, and women had greater serological responses against HPV-31 and -33 compared with men.

Background: Our goal in the present study was to investigate the prevalence and correlates of genital warts in a population of female sex workers in Mombasa, Kenya. Because of the high prevalence of human immunodeficiency virus type 1 (HIV-1) in this population, we were particularly interested in the association between HIV-1 infection and genital warts., Methods: We conducted a cross-sectional study of the prevalence and correlates of genital warts among high-risk women in Mombasa, Kenya. Between 2001 and 2007, 1182 women were enrolled, of whom 613 (51.4%) were HIV-1 seropositive. Chi square tests and logistic regression were used to examine the associations between genital warts and potential correlates., Results: Genital warts were identified on clinical examination in 27 (2.3%) women. Women who were HIV-1 seropositive were nearly 8 times as likely to have genital warts compared with HIV-1-seronegative women (odds ratio, 7.69; 95% confidence interval, 2.30-25.6)., Conclusion: Understanding the prevalence and correlates of genital warts will help to determine whether coverage for the wart-inducing subtypes 6 and 11 in a human papillomavirus vaccine is an important consideration in resource-limited countries.

Objective: Host defense and latency determinants in viral recurrent dermatologic infections are not entirely understood, as conventional protocols are inadequate to achieve fast healing and relapse prevention. Endogenously produced oxygen/nitrogen reactive species (ROS/RNS) are essential for antiviral immune defense, while their excess may aggravate skin inflammation. Here, we sought a nutritional approach capable of controlling ROS/RNS balance to accelerate recovery and inhibit recurrences of two mucocutaneous chronic DNA-virus infections., Methods: Two controlled clinical trials evaluated the feasibility of ROS/RNS-modulating nutriceutical dosages of coenzyme Q(10), RRR-α-tocopherol, selenium aspartate, and L-methionine associated with established therapies. Clinical trial 1 evaluated 68 patients with relapsing human papillomavirus skin warts treated with cryotherapy followed by 180 d of nutriceutical/placebo administration. Clinical trial 2 compared the combination of acyclovir followed by 90 d of nutriceutical administration versus acyclovir alone in patients with recurrences of herpes simplex genitalis (n = 60) or herpes zoster (n = 29). Viral DNA levels were assessed by polymer chain reaction, biomarkers of antiviral defense (peroxynitrite and IFNα/γ) and antioxidant capacity (lipophilic antioxidants and glutathione) were assayed by biochemical/enzyme-linked immunosorbent assay techniques in blood fractions., Results: In both trials, the nutriceutical induced significantly faster healing (P < 0.01-0.05) with reduced incidence of relapses (P < 0.05) as compared to control groups, which was confirmed by decreased viral load and increased antiviral cytokine and peroxynitrite plasma levels. Plasma antioxidant capacity was higher (P < 0.01) in the experimental versus control groups., Conclusions: Results document positive clinical outcomes of the selected nutriceutical associated with conventional protocols in the management of relapsing mucocutaneous human papillomavirus and herpes infections., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Few previous investigations on correlates of HPV vaccine uptake have included Hispanics, a group known to have a disproportionately high risk of cervical cancer., Methods: Rural Hispanic mothers of daughters aged 9-17 (n=78) were recruited at local community events to participate in a standardized Spanish-language survey that examined factors related to vaccine uptake., Results: Approximately 35% of the mothers reported that their daughter had received at least one dose of the vaccine. Mothers who had heard of the HPV vaccine were more likely to have a vaccinated daughter (p<.01). Mothers who thought their daughter's father would approve were more likely to have a vaccinated daughter (p=.004). Contrary to expectation, parents who believed that only one injection is necessary were more likely to have a vaccinated daughter (p=.009)., Conclusions: HPV vaccine education programs that target both parents are needed to ensure that Hispanic parents receive the complete HPV vaccine regimen.

The future incidence of cervical cancer is forecast to decline because of the remarkably effective prophylactic vaccines against human papillomaviruses. However, lack of access to these expensive vaccines in the developing countries where cervical cancer is most frequent, and the restricted genotypes these vaccines protect against, will limit their impact. Clearly, there is still a need for identifying other modalities for preventing HPV infections. Ready access to effective, inexpensive antivirals represents one potentially valuable approach to the prevention of genital HPV infections. We developed a well-validated high throughput screening (HTS) assay for identifying compounds that inhibit HPV infection and applied this assay to identify lead compounds that act by inhibiting an early step in infection. We screened over 40,000 small molecules that were available at the University of Wisconsin Small Molecule Screening Facility (UW-SMSF). The top 22 compounds were chosen for further analyses based upon the pharmacological property, scaffold diversity, strength of the inhibitory activity and lack of nonspecific cytotoxicity. Of these compounds, #13 and #14 had the most acceptable properties of low to submicromolar IC(50)'s and low cytotoxicity. Optimal antiviral activities were elicited by exposure of cells to the #13 and #14 during the initial 12 h following infection. Twenty-nine #13-like and 15 #14-like analogs were identified in silico and tested for their antiviral activities corresponded to the altered structures comparing to #13 and #14, informing on the pharmacophore structure of each compound. Studies indicate that both compounds inhibit infection post-entry., (Copyright © 2011 Elsevier B.V. All rights reserved.)

This article critically examines the proliferation of information on the human papillomavirus (HPV) vaccination as integral to contemporary processes of medicalization that take the young female body and her nascent sexuality as its primary object and target. We suggest that the recent introduction of voluntary HPV vaccination for girls, in North America and elsewhere, constitutes a form of neomedicalization (Batt & Lippman, 2010 ) that links risks for future disease (cervical cancer) with the transmission of a common, sexually transmitted infection (HPV). Informed by findings from a critical discourse analysis of Canadian English newspapers, magazines, and public information about HPV vaccination, our interest is on how the emergence of sexual relationships becomes constructed as a time fraught with risks to future health, and that must be managed through biotechnological intervention (vaccination). We suggest that this configuration of medicalization, rather than demarcate a new category of abnormality that can be treated with pharmaceutical or medical intervention, positions the emergence of sexuality itself as the basis of risk and pathologization. The article concludes by considering the implications of this form of medicalization for constructions of female sexuality and sexual health education.

Recent data demonstrate that human papillomavirus also plays a role in cancers other than ano-genital cancers, specifically head and neck cancers, and non-cancerous conditions such as recurrent respiratory papillomatosis. As more and more information about the role of infection in non-cervical diseases is amassed, additional questions about whether prophylactic human papillomavirus vaccines will effectively prevent these conditions are raised. This article reviews the epidemiology of oral human papillomavirus infection and the role of human papillomavirus in head and neck cancers. In addition, it will review the known clinical indications for human papillomavirus vaccination, and highlight other potential clinical targets for the vaccine that have not yet been demonstrated in clinical trials but for which there is biologic plausibility., (Copyright © 2011. Published by Elsevier Inc.)

Australia commenced an ongoing school based government funded human papillomaviruses (HPV) (cervical cancer prevention) vaccination program in April 2007 for adolescent females aged 12-13 years. In addition, up to December 31, 2009, a catch-up program for young females 13-26 years of age was offered: a school-based vaccination program was used to offer HPV vaccine to girls enrolled in school (14-17 years), and general practitioners or other community health provider offered vaccine to young women aged 18-26 years. To date, only the quadrivalent vaccine (HPV 6/11/16/18) has been utilized in the funded program. Acceptance of the vaccine is high with coverage of 3 doses of the HPV vaccine in the school age cohort around 70%, and just over 30% in the older age cohort. Since the vaccination program was initiated, a reduction in new cases of genital warts of 73% among vaccine eligible age females has been evidenced in STI clinics across Australia. A reduction of 44% of new cases in young males (not a part of the free program) was also documented during this same time period, suggesting significant herd immunity. Similarly, in the state of Victoria, a small but significant decrease in high grade abnormalities in Pap screening findings has been reported in young women<18 years for the period 2007-9, as compared to pre-vaccination. Challenges for the future include how we can sustain and improve HPV vaccination coverage in young Australian women, while maintaining cervical cancer screening participation and reviewing cervical cancer screening methods., (Copyright © 2011. Published by Elsevier Inc.)

Background: Cervical cancer has been extensively studied, as well as the various risk factors for that cancer. One such factor is the prolonged use of hormonal contraceptives., Objective: To report the biological, immunological and epidemiological findings arising from the use of oral contraceptives and their relation to cervical cancer., Material and Methods: Retrospective study based on information published in national and international literature., Conclusions: Controversy persists between the epidemiological data and experimental biological association between hormonal contraceptives and cancer induced by HPV. It is important to consider the biological findings because in Mexico the use of hormonal contraceptives is very broad and the number of cases of cervical cancer and only extensive epidemiological studies will clarify this controversy.

Scope: Observational studies have evaluated the relationship between green tea intake and cancers of the ovary and endometrium, but we are not aware of the published studies on green tea intake and risk of human papillomavirus (HPV)-related cancers of the cervix, vagina, or vulva., Methods and Results: A critical review of the published literature on tea intake and risk of ovarian and endometrial cancers was conducted. In meta-analyses, we report inverse associations for green tea intake and risk of ovarian cancer (odds ratio [OR]=0.66; 95% confidence interval [CI]: 0.54, 0.80), and for green tea and risk of endometrial cancer (OR=0.78, 95% CI: 0.62, 0.98). There was no association for black tea and ovarian cancer risk (OR=0.94, 95% CI: 0.87, 1.02) and a positive association with endometrial cancer risk (OR=1.20, 95% CI: 1.05, 1.38). We summarized the experimental evidence supporting the antiviral and immunomodulatory activities of green tea catechins, and results from randomized clinical trials that demonstrated green tea catechin efficacy on treatment of cervical lesions and external genital warts., Conclusion: Observational data support a protective role of green tea on risk of ovarian and endometrial cancers. Observational data are needed to evaluate whether green tea reduces risk of human papillomavirus-related cancers., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Vaccines against the human papillomavirus (HPV)--the primary cause of cervical cancer--target adolescent girls, many of whom have limited contact with health services. Countries in the Americas are beginning to use HPV vaccines to increase the impact of cervical cancer programs and as an entry point to broader health services for girls. This strategy opens new opportunities to improve lifelong health habits; encourage regular cervical cancer screening and treatment, when necessary; and offer associated services such as reproductive health and nutrition guidance. Some of the early experiences with this strategy illustrate challenges and opportunities that may arise with other new vaccines.

Background: Specific types of high risk Human papillomaviruses (HR-HPVs) particularly, HPV types 16 and 18 cause cervical cancer and while the two recently developed vaccines against these HPV types are prophylactic in nature, therapeutic options for treatment and management of already existing HPV infection are not available as yet. Because transcription factor, Activator Protein-1 (AP-1) plays a central role in HPV-mediated cervical carcinogenesis, we explored the possibility of its therapeutic targeting by berberine, a natural alkaloid derived from a medicinal plant species, Berberis which has been shown to possess anti-inflammatory and anti-cancer properties with no known toxicity; however, the effect of berberine against HPV has not been elucidated., Results: We studied the effect of berberine on HPV16-positive cervical cancer cell line, SiHa and HPV18-positive cervical cancer cell line, HeLa using electrophoretic mobility gel shift assays, western and northern blotting which showed that berberine could selectively inhibit constitutively activated AP-1 in a dose- and time-dependent manner and downregulates HPV oncogenes expression. Inhibition of AP-1 was also accompanied by changes in the composition of their DNA-binding complex. Berberine specifically downregulated expression of oncogenic c-Fos which was also absent in the AP-1 binding complex. Treatment with berberine resulted in repression of E6 and E7 levels and concomitant increase in p53 and Rb expression in both cell types. Berberine also suppressed expression of telomerase protein, hTERT, which translated into growth inhibition of cervical cancer cells. Interestingly, a higher concentration of berberine was found to reduce the cell viability through mitochondria-mediated pathway and induce apoptosis by activating caspase-3., Conclusion: These results indicate that berberine can effectively target both the host and viral factors responsible for development of cervical cancer through inhibition of AP-1 and blocking viral oncoproteins E6 and E7 expression. Inhibition of AP-1 activity by berberine may be one of the mechanisms responsible for the anti-HPV effect of berberine. We propose that berberine is a potentially promising compound for the treatment of cervical cancer infected with HPV.

Primary HPV prevention may be the key to reducing incidence and burden of cervical cancer particularly in resource-poor countries. Vaccination programmes are already established in several developed regions, but several grey areas stand in the path of similar success in developing countries. This review sought to identify challenges of HPV vaccination in developing countries and discuss vaccine use, pitfalls and controversies; areas requiring collaborative efforts were identified. A Pub Med search was done; key words included Human papilloma virus, HPV vaccine and sub-Saharan Africa. Other resources included locally-published articles and additional internet resources. The potential benefit of mass HPV vaccination appears enormous. However, the challenges of competing health demands, poverty, ignorance, religion, culture, weak health system, establishment of an effective intersectoral collaboration and underfunding must be overcome to make maximal vaccine uptake a reality. Education and effective communication is crucial in achieving successful immunization programmes.

Objective: A summary of postlicensure safety information of HPV vaccines from three sources: VigiBase, the global database of WHO's Programme for International Drug Monitoring, the VAERS report on Gardasil and the RIVM report on Cervarix., Method: all AEFI from the three sources were recalculated to a percentage of all AEFI reported for each of the two vaccines. And the safety profile was compared to the safety data in the SPC., Results: Comparison of relative AEFI reporting proportions in the global VigiBase database with VAERS for Gardasil and with RIVM for Cervarix shows a safety profile in VigiBase similar to the result of PMS on a national level in 2 countries., Conclusion: The post licensure safety profile of both vaccines is consistent with the data in the SPC of these vaccines.

Estrogen and its receptors are implicated in the promotion and prevention of various cancers. Although the uterine cervix is highly responsive to estrogen, the role of estrogen in cervical cancer, which is strongly associated with human papillomavirus (HPV) infections, is poorly understood. Recent studies in HPV transgenic mouse models provide evidence that estrogen and its nuclear receptor promote cervical cancer in combination with HPV oncogenes. Although epidemiological studies further support this hypothesis, there is little experimental data assessing the hormonal responsiveness of human cervical cancers. If these cancers are dependent on estrogen, then drugs targeting estrogen and its receptors could be effective in treating and/or preventing cervical cancer, the second leading cause of death by cancer among women worldwide., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

Background: With the recent introduction of a human papillomavirus (HPV) vaccine in Canada, it is important to establish surveillance and evaluation programs that not only track the uptake of the vaccine, but also assess its safety and its impact on: distribution of HPV type, cervical cancer screening programs, the incidence of anogenital warts, precancerous lesions and various cancers, and sexual behaviour., Data Sources and Methods: Administrative databases, registries and questionnaire information are being linked to identify people receiving the HPV vaccine and to develop an evaluation system., Interpretation: The availability of extensive linkable databases in Manitoba allows for the development of a comprehensive HPV vaccine surveillance and evaluation system that can address many of the questions related to the HPV vaccine. Aspects of the Manitoba surveillance and evaluation system could be implemented in other provinces that have similar databases.

Recurrent respiratory papillomatosis (RRP) is a rare disease in children and adults. It is characterized by proliferation of benign squamous cell papillomas within the respiratory-digestive tract, predominantly the larynx. RRP is caused by oral infection with human papilloma virus (HPV) types 6 or 11. In aggressive disease, which within few months or even weeks requires multiple surgical interventions to remove papillomas, residual impairment of voice and breathing is almost inevitable. Nowadays immune stimulation with interferon alpha or topic application of Cidofovir are recommended to lower the recurrence rate in aggressive disease but vaccination against mumps virus and photodynamic therapies has also been administered. The recently developed tetravalent HPV vaccine Gardasil induces neutralizing antibodies against capsid antigens of the HPV types 16 and 18, which are associated with cervical cancer, as well as against types 6 and 11, which are associated with condylomata acuminata und respiratory papillomatosis. The vaccine has been shown to be safe and highly immunogenic. It can efficaciously prevent new genital infections by one of the four vaccine types as well as the epithelial lesions induced by them. However, the vaccine had no effect against pre-existing genital infections or lesions. Here we propose the hypothesis that HPV vaccination could have a therapeutic effect in RRP by preventing new papilloma formation at additional sites. First case reports on Gardasil vaccination in juvenile as well as adult onset RRP have become available and their serological findings are presented here. In view of the low risk of this adjuvant immunotherapy a larger controlled multicentric trial is proposed to verify this hypothesis.

Prophylactic HPV L1 VLP quadrivalent and bivalent vaccines have a great importance for patients seen by dermatologists and venereologists. Both vaccines protect against HPV16- and HPV 18-associated anogenital cancers, as well as cancers of the mouth, the upper respiratory tract and skin, especially of the fingers and periungual region. The quadrivalent HPV6, 11, 16, 18 vaccine also prevents anogenital warts (condylomata acuminata) which are the most common benign tumors of this body region. HPV-vaccination (Gardasil) has been approved in Germany and other European Countries since October 2006 for young girls between 9-16 and young women between 16-26 years of age. Many experts feel that boys and young men should also be vaccinated. Men would profit from a vaccine that protects against HPV infections, especially anogenital warts, as well as penile and anal carcinomas. In immunosuppressed organ transplant recipients and HIV-positive patients. HPV disease can be widespread, chronic and often may rapidly progress to malignant tumors. Thus, these individuals would greatly benefit from prophylactic HPV immunization.

In the United States, there are 11,150 cases and 3670 deaths projected due to invasive cervical cancer for 2007. Approximately 500,000 new cases and 274,000 deaths will occur in women throughout the world. Human papillomavirus (HPV) has been designated by the World Health Organization (WHO) as a "necessary cause" of cervical cancer. There are 6.2 million new cases of HPV diagnosed each year. In addition to cervical cancer, the virus has also been implicated in vaginal, vulvar, penile, anal, and head and neck cancers. Current methods for prevention of cervical cancer include Pap smears, HPV testing, ablative procedures, cervical conization, and hysterectomy. These are costly as well as invasive. The HPV vaccine is the most recent breakthrough for the prevention of cervical cancer. The quadrivalent HPV vaccine (Gardasil) covers types 6, 11, 16, & 18. The bivalent vaccine (Cervarix) covers types 16 & 18, and is expected to come out in the early part of 2007. Approximately 70% of cervical cancer is caused by HPV types 16 & 18. HPV types 6 &11 are responsible for 90% of anogenital warts. Females of ages 11-12 and those prior to their sexual debut should be vaccinated, with all females in the age range of 9-26 also eligible. This vaccination strategy can prevent the above HPV infections, cervical dysplasia, and possibly cervical cancer.

Objective: To evaluate the value of 85% trichloroacetic acid (TCA) in the treatment of human papillomavirus (HPV)-associated genital warts of the external genitalia and to detect the recurrence rate and side effects of this therapeutic regimen., Study Design: All patients with a suspected HPV-related papillary vulvar lesion after initial examination underwent vulvoscopic evaluation with a magnification of 8-20x using acetic acid and toluidine blue. Under local anesthesia, biopsies were taken from acuminate or papillary warts for histopathologic confirmation and from suspicious areas to exclude preinvasive or invasive diseases. Following histopathologic diagnosis, patients were treated with 85% TCA., Results: Overall, 51 patients with isolated vulvar and/or perianal genital warts were included. Of those patients, 11 (21.5%) had acuminate and 40 (78.5%) had papular genital warts. All the women had lesions of the labia minora. The other localizations were as follows: labia majora, 18 (35.3%); lateral vulva, 5 (9.8%); clitoris, 9 (17.6%); fourchette, 16 (31.3%); and perianal area, 7 (13.7%). All lesions were successfully treated by the end of the treatment period (median, 4; range 2-5). None of the patients had recurrence or new lesions during the 6-month follow-up period. In the second 6 months, 9 patients (17.6%) were diagnosed with recurrent lesions. Although all the patients experienced transient burning pain during therapy, none of them discontinued the therapy. Ulceration was observed in 8 patients (15.6%). Of those patients only 3 had permanent scarring (5.8%)., Conclusion: We recommend the use of TCA in patients with external genital warts, especially for mild to moderate cases. It is associated with a high success rate and low morbidity if sufficient care is taken during application.

Human papillomaviruses (HPV) infect stratified epithelia and restrict expression of late capsid genes to highly differentiated cells. In order to begin to understand the processes regulating HPV 31 infection we examined the synthesis of the HPV 31 capsid proteins, L1 and L2, using heterologous expression systems. Similar to studies in HPV 16, expression of wild type HPV 31 L1 and L2 from heterologous promoters resulted in very low levels of synthesis. In contrast, modification of the codons in the capsid genes to ones more commonly used in cellular genes resulted in high-level synthesis. Through the use of chimeric proteins that fused fragments of wild type L1 to Green Fluorescent Protein (GFP) coding sequences, a short region was identified that was sufficient to inhibit high level synthesis and similar elements were detected in L2. One element was localized to the 3' end of the L1 gene while a series of elements were localized at the 3' end of the L2 coding sequences. These observations are most consistent with negative RNA regulatory elements controlling the levels of L1 and L2 synthesis that are distinct from those identified in HPV 16. Expression vectors for the codon modified HPV 31 capsid proteins were then transfected together with GFP reporter plasmids to generate HPV 31 pseudoviruses. Infection of cells with HPV 31 pseudoviruses in the presence of the inhibitors, chlorpromazine, nystatin or methyl-beta-cyclodextrin, demonstrated that HPV 31, like HPV 16, enters human and monkey cells through a clathrin-mediated pathway rather than through caveolae as previously reported. This suggests that high-risk HPV types may enter cells through common mechanisms.