Papiloma Conjuntival: revisión bibliográfica / Conjunctival Papilloma: a literature review

Objetivo: El objetivo de la realización del presente artículo de revisión bibliográfica es analizar las características del Papiloma conjuntival como: el pronóstico, prevalencia, relación con el VPH, diagnóstico, tratamiento e importancia que representa la presencia del mismo. Métodos: El siguiente artículo se realizó mediante la búsqueda de artículos científicos en español e inglés, mismos que fueron obtenidos a través de base de datos como Scopus, PubMed y Google Academic. Se hizo usó de la plataforma virtual de la biblioteca católica de Cuenca utilizando comandos de búsqueda avanzada (""), AND, OR. Finalmente se incluyeron 15 artículos dentro de la revisión bibliográfica. Para el trabajo conjunto de los colaboradores se hizo uso de la plataforma Google Drive. Resultados: Papiloma conjuntival es un tumor de células escamosas benigno de la conjuntiva con una tendencia mínima a la malignidad. Estos tumores están relacionados con el VPH específicamente los tipos VI y XI. Para obtener un diagnóstico es importante realizar una anamnesis y un examen oftalmológico exhaustivo, una biopsia posterior a la extirpación de la lesión, la tomografía de coherencia óptica de alta definición (HR-OCT), y la biomicroscopia ultrasónica (UBM). El MSP, ha elaborado una iniciativa denominada "Programa Ampliado de Inmunizaciones (PAI)", mismo que consiste en el proceso de vacunación de la población femenina de 9, 10 y 11 años pertenecientes a escuelas públicas y privadas. Conclusiones: Es importante que las instituciones educativas fomenten más la salud ocular porque al momento de que existe un contagio de VPH hay riesgo de tener papiloma conjuntival y las personas desconocen este medio de transmisión. Además, se debe promover la vacunación en niños porque cualquier género es propenso a adquirir el VPH

Objective: The aim of this literature review article is to analyze the characteristics of: conjunctival papilloma such as prognosis, prevalence, relationship with HPV, diagnosis, treatment and importance of its presence. Methods: The following article was carried out by searching scientific articles in Spanish and English, which were obtained through databases such as Scopus, PubMed and Google Academic. We used the virtual platform of the Catholic Library of Cuenca using advanced search commands (""), AND, OR. Finally, 15 articles were included in the biliographic review. For the joint work of the collaborators, use was made of the Google Drive platform. Results: Conjunctival papilloma is a benign squamous cell tumor of the conjunctiva with a minimal tendency to malignancy. These tumors are related to HPV specifically types VI and XI. To obtain a diagnosis it is important to perform a thorough anamnesis and ophthalmologic examination, a biopsy after removal of the lesion, high-definition optical coherence tomography (HR-OCT), and ultrasonic biomicroscopy (UBM). The MSP has developed an initiative called "Expanded Program of Immunizations (PAI)", same that consists of the vaccination process of the female population of 9, 10 and 11 years old belonging to public and private schools. Conclusions: It is important that educational institutions promote more eye health because when there is an HPV infection there is a risk of having conjunctival papilloma and people are unaware of this means of transmission. In addition, vaccination should be promoted in children because any gender is prone to acquire HPV.

Clinical Characteristics of Human Papillomavirus Infection in the Male Genital Tract.

Objective: This study aims to understand the clinical characteristics of male HPV infection and provide data and information for the prevention and health of the male and female reproductive tracts in the region. Methods: A total of 390 male patients who underwent HPV examinations in outpatient clinics and physical examinations in 363 hospitals from December 2017 to May 2022 were selected. Samples were collected, and HPV genotyping was performed using multiplex fluorescent PCR. The HPV infection rate, genotype distribution, age distribution, and clinical symptom distribution were analyzed. Results: Out of 3,816 samples, the total HPV infection rate was 47.44% (185/390). The HPV infection rate in the symptomatic group was 57.09% (141/247), significantly higher than that in the asymptomatic group (P < .01). Among the subtypes, HPV6 accounted for the highest proportion (31.03%, 90/290), followed by HPV11 (14.14%, 41/290) and HPV52 (8.62%, 25/290). Types 6 and 11 were mainly concentrated in the symptomatic group (91.11%, 85.37%). The highest positive rate was observed in the 17-30-year-old group (45.41%, 85/185), followed by the 31-40-year-old group (28.11%, 52/185). The proportion of HPV infections with clinical symptoms of abnormal growth was 84.40% (119/141). HPV6 or/and HPV11 infections were mainly concentrated in the abnormal growth group, accounting for 90.76% (108/113). Conclusions: The rates of male HPV infection are high, particularly among individuals aged 17-40. Low-risk infections (types 6 and 11) cause male reproductive tract symptoms, including abnormal growth. High-risk infection (HPV52) correlates with local women's HPV subtype distribution and potential transmission. Therefore, screening for male HPV infection is crucial in preventing cervical cancer. Authorities should promote the development and early use of male HPV vaccines.

Characterization and comparative analysis of phosphorylation patterns in HPV18 and HPV11 E1 helicases: Implications for viral genome replication.

The genome of human papillomaviruses (HPVs) encodes the E1 replication factor, whose biological activities are regulated by cellular protein kinases. Here, the phosphorylation pattern of the E1 helicase of oncogenic mucosotropic HPV18 was investigated both in vitro and in vivo. Four serine residues located in a short peptide within a localization regulatory region were found to be phosphorylated in both experimental settings. We demonstrate that this peptide is targeted in vitro by various protein kinases, including CK2, PKA, and CKD2/cyclin A/B/E complexes. Through point mutagenesis, we show that phosphorylation of this region is essential for E1 subcellular localization, the interaction of E1 with the E2 protein, and replication of the HPV18 genome. Furthermore, we demonstrate the functional conservation of this phosphorylation across the E1 proteins of the low-risk mucosotropic HPV11 and high-risk cutaneotropic HPV5. These findings provide deeper insights into the phosphorylation-mediated regulation of biological activities of the E1 protein.

Preclinical Models of Laryngeal Papillomavirus Infection: A Scoping Review.

OBJECTIVE: Laryngeal human papillomavirus (HPV) infection causes recurrent respiratory papillomatosis (RRP) and accounts for up to 25% of laryngeal cancers. Lack of satisfactory preclinical models is one reason that treatments for these diseases are limited. We sought to assess the literature describing preclinical models of laryngeal papillomavirus infection. DATA SOURCES: PubMed, Web of Science, and Scopus were searched from the inception of database through October 2022. REVIEW METHODS: Studies searched were screened by two investigators. Eligible studies were peer-reviewed, published in English, presented original data, and described attempted models of laryngeal papillomavirus infection. Data examined included type of papillomavirus, infection model, and results including success rate, disease phenotype, and viral retention. RESULTS: After screening 440 citations and 138 full-text studies, 77 studies published between 1923 and 2022 were included. Models used low-risk HPV or RRP (n = 51 studies), high-risk HPV or laryngeal cancer (n = 16), both low- and high-risk HPV (n = 1), and animal papillomaviruses (n = 9). For RRP, 2D and 3D cell culture models and xenografts retained disease phenotypes and HPV DNA in the short term. Two laryngeal cancer cell lines were consistently HPV-positive in multiple studies. Animal laryngeal infections with animal papillomaviruses resulted in disease and long-term retention of viral DNA. CONCLUSIONS: Laryngeal papillomavirus infection models have been researched for 100 years and primarily involve low-risk HPV. Most models lose viral DNA after a short duration. Future work is needed to model persistent and recurrent diseases, consistent with RRP and HPV-positive laryngeal cancer. LEVEL OF EVIDENCE: NA Laryngoscope, 133:3256-3268, 2023.

Interim Results of a Phase 1/2 Open-Label Study of INO-3107 for HPV-6 and/or HPV-11-Associated Recurrent Respiratory Papillomatosis.

OBJECTIVE: To evaluate the safety, immunogenicity, and efficacy of INO-3107, a DNA immunotherapy designed to elicit targeted T-cell responses against human papillomavirus (HPV) types 6 and 11, in adult patients with recurrent respiratory papillomatosis (RRP; NCT04398433). METHODS: Eligible patients required ≥2 surgical interventions for RRP in the year preceding dosing. INO-3107 was administered by intramuscular (IM) injection followed by electroporation (EP) on weeks 0, 3, 6, and 9. Patients underwent surgical debulking within 14 days prior to first dose, with office laryngoscopy and staging at screening and weeks 6, 11, 26, and 52. Primary endpoint was safety and tolerability, as assessed by treatment-emergent adverse events (TEAEs). Secondary endpoints included frequency of surgical interventions post-INO-3107 and cellular immune responses. RESULTS: An initial cohort of 21 patients was enrolled between October 2020 and August 2021. Fifteen (71.4%) patients had ≥1 TEAE; 11 (52.4%) were Grade 1, and 3 (14.3%) were Grade 3 (none treatment related). The most frequently reported TEAE was injection site or procedural pain (n = 8; 38.1%). Sixteen (76.2%) patients had fewer surgical interventions in the year following INO-3107 administration, with a median decrease of 3 interventions versus the preceding year. The RRP severity score, modified by Pransky, showed improvement from baseline to week 52. INO-3107 induced durable cellular responses against HPV-6 and HPV-11, with an increase in activated CD4 and CD8 T cells and CD8 cells with lytic potential. CONCLUSION: The data suggest that INO-3107 administered by IM/EP is tolerable and immunogenic and provides clinical benefit to adults with RRP. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:3087-3093, 2023.

Association between human papillomavirus particle production and the severity of recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) has a wide range of severity. We investigate the relationship between human papillomavirus (HPV) particle production and severity of RRP. From September 2005 to June 2021, 68 RRP samples (from 29 patients) were included. HPV type was determined. HPV viral load, physical status, and demographic and clinical characteristics were assessed. Immunohistochemistry (IHC) was performed for p16, Ki-67, L1, and E4. We used NanoSuit-CLEM (correlative light and electron microscopy) and transmission electron microscopy (TEM) to examine the samples. The total number of surgeries in HPV-positive and HPV-negative cases were 3.78 (n = 55/68, range: 1-16) and 1.30 (n = 13/68, range: 1-3), respectively (p = 0.02). IHC showed that L1 and E4 were correlated and expressed on the tumour surface. NanoSuit-CLEM and TEM revealed HPV particles in L1-positive nuclei. L1 IHC-positive cases had a shorter surgical interval (p < 0.01) and more frequent surgeries (p = 0.04). P16 IHC, viral load, and physical status were not associated with disease severity. This study visualised HPV particle production in RRP for the first time. Persistent HPV particle infection was associated with severity. We suggest L1 IHC for evaluating RRP severity in addition to the Derkay score.

Epidemiology of human papillomavirus on condyloma acuminatum in Shandong Province，China.

Condyloma acuminatum (CA) is a sexually transmitted disease (STD) caused by human papillomavirus (HPV) infection. It is important to study the prevalence and distribution of HPV genotypes before implementing the HPV vaccination program. Therefore, the aim of this study was to evaluate the epidemiological characteristics of CA cases and the distribution of HPV genotypes in Shandong Province, China. One-to-one questionnaire surveys were conducted on all patients diagnosed with CA in sentinel hospitals from Shandong Province, China. HPV genotypes were determined using the polymerase chain reaction (PCR)-reverse dot blot hybridization method. The study enrolled 1185 patients (870 males and 315 females) and found that CA patients are mainly males and sexually active people between the ages of 20 and 40. Recurrence occurred in 34.7% patients. Among the 880 CA patients who underwent HPV typing, the HPV test positivity rate was 91.4%. In these cases, low-risk (LR) HPV infection was predominant, with an infection rate of 91.3%, while high-risk (HR) HPV genotypes were found in 53.5% patients. The most frequent HPV genotypes encountered were HPV6 (57.8%), HPV11 (37.2%), HPV16 (13.7%), and HPV42 (10.3%). HPV6 and/or HPV11 are the main infections in all patients, and more than half of the patients are coinfected with HR-HPV. However, unlike other regions, HPV42 has a higher prevalence rate among CA patients in Shandong Province and is a nonvaccine HPV genotype. Therefore, regular HPV typing helps to understand the characteristics of specific genotypes and the choice of the best type for vaccine coverage.

Human papillomavirus vaccination in Africa: An airway perspective.

INTRODUCTION: Recurrent respiratory papillomatosis (RRP) is a chronic condition caused by Human papillomavirus six (HPV-6) and HPV-11 that involves the respiratory tract. Disease severity ranges from mild (hoarseness), through to severe (stridor, respiratory distress and airway emergencies). Africa has the fastest growing and youngest population of all the continents. It also has the greatest burden of cervical cancer. There is an association with infection of the oncogenic HPV strains and the strains responsible for RRP. It is reasonable to conclude that although RRP may be underestimated in low-to-middle-income countries, it poses a considerable health risk to Africa. The primary aim of this project was to assess the suitability of HPV vaccination coverage on the African continent. METHODS: A prospective study was designed to consist of an online survey. It was distributed to 135 African otolaryngologists. Questions focussed on HPV vaccination programmes; whether they were government directed; and their rollout. Information from countries that had multiple otolaryngologists respond to the survey were compared. Additionally, data review and corroboration were performed. RESULTS: There were 58 (43%) participants from 19 countries. Nine countries reported a national vaccination programme (NVP), five used Cervarix; four used quadrivalent Gardasil. Collateral data revealed 18 of 54 countries had NVP in Africa and 26 countries had completed HPV vaccine pilot or demonstration projects. CONCLUSIONS: HPV vaccination in Africa should be urgently re-evaluated to include the HPV-6 and HPV-11 strains that cause JORRP, which have not been recognised during national vaccination programme planning.

Restricted Recruitment of NK Cells with Impaired Function Is Caused by HPV-Driven Immunosuppressive Microenvironment of Papillomas in Aggressive Juvenile-Onset Recurrent Respiratory Papillomatosis Patients.

Laryngopharynx epithelium neoplasia induced by HPV6/11 infection in juvenile-onset recurrent respiratory papillomatosis (JO-RRP) causes a great health issue characteristic of frequent relapse and aggressive disease progression. Local cell-mediated immunity shaped by the recruitment and activation of cytotoxic effector cells is critical for viral clearance. In this study, we found that NK cells in the papillomas of aggressive JO-RRP patients, in contrast to massive infiltrated T cells, were scarce in number and impaired in activation and cytotoxicity as they were in peripheral blood. Data from cell infiltration analysis indicated that the migration of NK cell to papilloma was restricted in aggressive JO-RRP patients. Further study showed that the skewed chemokine expression in the papillomas and elevated ICAM-1 expression in hyperplastic epithelia cells favored the T cell but not NK cell recruitment in aggressive JO-RRP patients. In parallel to the increased CD3+ T cells, we observed a dramatical increase in Tregs and Treg-promoting cytokines such as IL-4, IL-10 and TGFß in papillomas of aggressive JO-RRP patients. Our study suggested that likely initialized by the intrinsic change in neoplastic epithelial cells with persistent HPV infection, the aggressive papillomas built an entry barrier for NK cell infiltration and formed an immunosuppressive clump to fend off the immune attack from intra-papillomas NK cells. IMPORTANCE Frequent relapse and aggressive disease progression of juvenile-onset recurrent respiratory papillomatosis (JO-RRP) pose a great challenge to the complete remission of HPV 6/11 related laryngeal neoplasia. Local immune responses in papillomas are more relevant to the disease control considering the locale infected restriction of HPV virus in epitheliums. In our study, the restricted NK cell number and reduced expression of activating NKp30 receptor suggested one possible mechanism underlying impaired NK cell defense ability in aggressive JO-RRP papillomas. Meanwhile, the negative impact of HPV persistent infection on NK cell number and function represented yet another example of a chronic pathogen subverting NK cell behavior, affirming a potentially important role for NK cells in viral containment. Further, the skewed chemokine/cytokine expression in the papillomas and the elevated adhesion molecules expression in hyperplastic epithelia cells provided important clues for understanding blocked infiltration and antiviral dysfunction of NK cells in papilloma.

Systematic review of the use of human papillomavirus vaccine as adjuvant therapy for juvenile-onset recurrent respiratory papillomatosis.

INTRODUCTION: Juvenile-onset RRP (JoRRP) is considered a rare disease with high morbidity and healthcare costs. The management of RRP has received much scientific attention in recent years and several treatment methodologies have been explored, including therapeutic use of HPV vaccine. There has been increasing interest in the off-label use of the vaccine in virus-induced disease processes such as RRP, due to its immunomodulatory effect and activating role on the innate and adaptive immune system. This review explores the efficacy of the HPV vaccination as a therapeutic tool in the pediatric population. METHODS: The review of the English literature included three electronic databases, PubMed, SCOPUS, and Cochrane, without publication date restrictions. Studies and reports identified by the database search were reviewed and assessed by two independent reviewers. RESULTS: The literature searches identified 768 unique citations, from which 204 duplicates were removed (n = 564). A total of 547 articles were excluded as they did not meet our inclusion criteria. A total of 12 studies (3 experimental studies, 3 case series, 6 case reports) that met the inclusion criteria and reported one or more of the outcomes of interest were included for our review. The assessment of the outcome measures evaluated (number of surgeries during the follow-up period, ISI, SPM, Derkay or severity scores, and remission status) revealed that eight out of 12 studies included in the review showed varying degrees of potential benefits from the administration of the vaccine as a treatment modality compared to surgical interventions and/or concurrent adjuvant therapies alone. CONCLUSION: We conclude that while the therapeutic use of HPV vaccination has shown promise for some JoRRP patients, it overall remains uncertain with the currently available data. There is a need for a prospective multi-centric trial with a larger sample size to fully characterize the potential use of the vaccine in the management of JoRRP.

Tumor de Buschke ­ Löwenstein: Presentación de un Caso y Revisión Bibliográfica / Buschke ­ Löwenstein Tumor: A Case Report and Review of the Literature

Introducción: El tumor de Buschke ­ Lowenstein (TBL) es enfermedad de transmisión sexual causada por el virus del papiloma humano (VPH), descrita como una forma intermedia entre un condiloma acuminado y un carcinoma de células escamosas. Afecta principalmente al área genital y anorrectal, posee capacidad de transformación maligna y una alta tasa de recurrencia. La cirugía es el tratamiento de primera línea. Caso clínico: Presentamos el caso de un paciente masculino de 27 años con lesiones verrucosas de crecimiento progresivo en el área inguinal y genital. Mediante la correlación clínico-patológica se llegó al diagnóstico de TBL. Tras discusión en comité multidisciplinario se declaró irresecable y se resolvió tratamiento con radioterapia, además vacunación terapéutica contra el VPH, tanto sistémica como intralesional. Conclusión: El TBL es localmente agresivo y de difícil tratamiento, por lo que la prevención contra el VPH es fundamental. La vacunación terapéutica en conjunto con la radioterapia ofreció mejoría clínica.

Introduction: Buschke-Lowenstein tumor (BLT) is a sexually transmitted disease caused by the human papillomavirus (HPV), described as an intermediate form between condyloma acuminata and squamous cell carcinoma. It mainly affects the genital and anorectal areas and has the capacity for malignant transformation and a high recurrence rate. Surgery is the first-line treatment. Clinical case: We present the case of a 27-year-old male patient with warty lesions of progressive growth in the inguinal and genital areas. Through the clinical-pathological correlation, the diagnosis of BLT was reached. After discussion in a multidisciplinary committee, it was declared unresectable, and treatment with radiotherapy was resolved, in addition to therapeutic vaccination against HPV, both systemic and intralesional. Conclusion: BLT is locally aggressive and challenging to treat, so prevention against HPV is essential. Therapeutic vaccination in conjunction with radiotherapy offered clinical improvement.

Virus del papiloma humano en varones menores de cuatro años / Human papillomavirus in boys under 4-year old

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Transcriptomic Landscape of Gene Expression Profiles and Pathways in Juvenile-Onset Recurrent Respiratory Papillomatosis Tumor Tissues and Human Papillomavirus 6 and 11 E6- and E7-Overexpressing Head and Neck Squamous Cell Carcinoma Cell Lines.

Juvenile-onset recurrent respiratory papillomatosis (JORRP) is the most common benign laryngeal neoplasm in children and is considered to be primarily caused by human papillomavirus (HPV) types 6 and 11. In the present study, we performed RNA sequencing (RNA-seq) of 8 tumors and 4 adjacent nontumor tissues to explore the transcriptional profiles of JORRP tumors. A total of 1,151 upregulated genes involved in the interleukin-17 (IL-17) signaling pathway and 1,620 downregulated genes involved in dysregulated inflammatory responses were reported. Immunohistochemistry (IHC) assays confirmed the upregulation of IL-17C in JORRP tumors compared with paired adjacent nontumor tissues. Real-time PCR (RT-PCR) assays showed positive correlations between CXCL1 (CXC chemokine ligands 1) and CXCL8 and the Derkay Clinic Score of JORRP patients. We further overexpressed the HPV6 or HPV11 E6 and E7 oncogenes in SNU-1076 head and neck squamous cell carcinoma (HNSCC) cell lines and carried out RNA-seq. We found that HPV6-E6-E7 gene overexpression resulted in only 16 upregulated genes and 1 downregulated gene; however, HPV11-E6-E7 gene overexpression resulted in 1,776 upregulated genes and 461 downregulated genes compared with the control cell lines. The differentially expressed genes (DEGs) of HPV11-E6-E7 gene overexpression were positively enriched in the DNA replication-related terms by Gene Ontology (GO) analysis and the IL-17 signaling pathway by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Taken together, our present findings revealed IL-17 signaling pathway-related gene profiles that might contribute to disease pathogenesis and that the HPV11 E6 and E7 oncogenes promote disease progression by enhancing tumor growth and activating the IL-17 signaling pathway in JORRP patients. IMPORTANCE Juvenile-onset recurrent respiratory papillomatosis (JORRP) is primarily caused by human papillomavirus 6 (HPV6) and HPV11 infection; however, the gene signatures of tumors are currently less understood. In the present study, we performed RNA sequencing and found upregulated genes associated with the IL-17 signaling pathway and downregulated genes associated with inflammatory-related pathways. Further RNA sequencing was performed in HPV6-E6-E7- or HPV11-E6-E7-overexpressing SNU-1076 HNSCC cells lines to explore the potential pathogenic molecular mechanisms of HPV virus. We found that HPV11-E6-E7 overexpression resulted in gene expression related to DNA replication and the IL-17 signaling pathway. Our results suggested enriched that the IL-17 signaling pathway resulting from HPV11 infection might contribute to JORRP pathogenesis.

Comprehensive multiomic characterization of human papillomavirus-driven recurrent respiratory papillomatosis reveals distinct molecular subtypes.

Recurrent respiratory papillomatosis (RRP) is a debilitating neoplastic disorder of the upper aerodigestive tract caused by chronic infection with low-risk human papillomavirus types 6 or 11. Patients with severe RRP can require hundreds of lifetime surgeries to control their disease and pulmonary papillomatosis can be fatal. Here we report the comprehensive genomic and transcriptomic characterization of respiratory papillomas. We discovered and characterized distinct subtypes with transcriptional resemblance to either a basal or differentiated cell state that associate with disease aggressiveness and differ in key molecular, immune and APOBEC mutagenesis profiles. Through integrated comparison with high-risk HPV-associated head and neck squamous cell carcinoma, our analysis revealed divergent molecular and immune papilloma subtypes that form independent of underlying genomic alterations. Cumulatively our results support the development of dysregulated cellular proliferation and suppressed anti-viral immunity through distinct programs of squamous cell differentiation and associated expression of low-risk HPV genes. These analyses provide insight into the pathogenesis of respiratory papillomas and provide a foundation for the development of therapeutic strategies.

Development of Antibodies against HPV-6 and HPV-11 for the Study of Laryngeal Papilloma.

Laryngeal papilloma (LP), which is associated with infection by human papillomavirus (HPV)-6 or -11, displays aggressive growth. The precise molecular mechanism underlying the tumorigenesis of LP has yet to be uncovered. Building on our earlier research into HPV-6, in this study, the viral gene expression of HPV-11 was investigated by quantitative PCR and DNA/RNA in situ hybridization. Additionally, newly developed antibodies against the E4 protein of HPV-6 and HPV-11 were evaluated by immunohistochemistry. The average viral load of HPV-11 in LP was 1.95 ± 0.66 × 105 copies/ng DNA, and 88% of HPV mRNA expression was found to be E4, E5a, and E5b mRNAs. According to RNA in situ hybridization, E4 and E5b mRNAs were expressed from the middle to upper part of the epithelium. E4 immunohistochemistry revealed a wide positive reaction in the upper cell layer in line with E4 mRNA expression. Other head and neck lesions with HPV-11 infection also showed a positive reaction in E4 immunohistochemistry. The distribution pattern of HPV DNA, viral mRNA, and E4 protein in LP with HPV-11 infection was quite similar to that of HPV-6. Therefore, it might be possible to apply these E4-specific antibodies in other functional studies as well as clinical applications, including targeted molecular therapies in patients with HPV-6 and HPV-11 infection.

Anogenital giant condyloma in an infant with liver transplantation.

Human papillomavirus (HPV) types 6 and 11 were detected in a 3-year-old girl with extensive anogenital condylomata. Although sexual abuse must be considered, non-sexual transmission is evident in at least 57% of children with anogenital warts. Perinatal transmission may occur in approximately 24.5% of infants born to HPV-positive mothers. We present an immunosuppressed child with giant condylomata and discuss transmission, work up, and treatment.

A novel recombinant protein vaccine containing the different E7 proteins of the HPV16, 18, 6, 11 E7 linked to the HIV-1 Tat (47-57) improve cytotoxic immune responses.

OBJECTIVES: Human papillomavirus infection (HPV) is the most common viral infection which is causes of cervical, penal, vulvar, anal and, oropharyngeal cancer. E7 protein of HPV is a suitable target for induction of T cell responses and controlling HPV-related cancer. The aim of the current study was to designed and evaluated a novel fusion protein containing the different E7 proteins of the HPV 16, 18, 6 and 11, linked to the cell-penetrating peptide HIV-1 Tat 49-57, in order to improve cytotoxic immune responses in in-vitro and in-vivo. RESULTS: In this study whole sequence of HPV16,18,6,11 E7-Tat (47-57) and HPV16,18,6,11 E7 cloned into the vector and expressed in E. coli (BL21). The purified protein was confirmed by SDS page and western blotting and then injected into the C57BL/6 mice. The efficiency of the fusion protein vaccine was assessed by antibody response assay, cytokine assay (IL-4 and IFN-γ), CD + 8 cytotoxicity assay and tumor challenge experiment. Result showed that fusion proteins containing Adjuvant (IFA,CFA) could express higher titer of antibody. Also, we showed that vaccination with E7-Tat and, E7-Tat-ADJ induced high frequencies of E7-specific CD8 + T cells and CD107a expression as well as IFN-γ level and enhanced long-term survival in the therapeutic animal models. CONCLUSION: Our finding suggested that this novel fusion protein vaccine was able to induce therapeutic efficacy and immunogenicity by improving CD8 + T cell in TC-1 tumor bearing mice; so this vaccine may be appreciated for research against HPV and tumor immunotherapies.

Effect of E2 and long control region polymorphisms on disease severity in human papillomavirus type 11 mediated mucosal disease: Protein modelling and functional analysis.

Interaction of the long control region (LCR) and the E2 protein of HPV11s was studied by in silico modelling and in vitro functional analysis. Genomes of HPV11s from fifteen (six known and nine novel) patients (two solitary papillomas, eleven respiratory papillomatoses of different severity, one condyloma acuminatum and one cervical atypia) were sequenced; E2 polymorphisms were analysed in silico by protein modelling. E2 and LCR variants were cloned into pcDNA3.1+ expression vector and into pALuc reporter vector, respectively, transfected to HEp2 cells alone or in different combinations and the luciferase activity was measured. In the E2, the ubiquitous polymorphism K308R caused stronger binding between the dimers but did not alter DNA binding; E2s with this polymorphism were significantly less efficient than the reference in promoting LCR activity. The unique polymorphism Q86K changed the negative surface charge of E2 (Q86) to positive (K86). The unique polymorphisms S245F and N247T in the hinge region disrupt a probable phosphorylation site in a RXXS motif targeted by protein kinase A and B, but do not affect directly the amino acids critical to nuclear transport. Both unique patterns partly restored the LCR activating potential disrupted by K308R. A unique E2/E4 ORF with a 58-bp deletion leading to a frameshift and an early stop codon resulted in a practically nonfunctional E2, and was associated with a papillomatosis with dysplasia. When testing existing LCR-E2 combinations, LCR with intrinsically lower enhancer capacity was only marginally activated by its E2 (R308 and the deletion mutant), and did not significantly exceed the activity of the reference LCR without E2. Combined with more potent LCRs associated with more severe disease, the activity was significantly higher, but still significantly lower than LCRs with reference E2. In summary, LCR-E2 interaction determined by their polymorphisms may explain, at least partly, differences in disease severity.

Co-expression of low-risk HPV E6/E7 and EBV LMP-1 leads to precancerous lesions by DNA damage.

BACKGROUND: Low-risk human papillomavirus (HPV), such as types 6 and 11, is considered non-oncogenic, but these types have been detected in oral cancer tissue samples, suggesting their possible involvement in oral carcinogenesis. Because double infection of high-risk HPV and Epstein-Barr virus (EBV) is known to be involved in oral carcinogenesis, we hypothesized that low-risk HPV and EBV co-infection can transform the oral cells. To verify our hypothesis, we evaluated the transformation activity of cell lines expressing both low-risk HPV E6/E7 and EBV LMP-1. METHODS: We transduced HPV6, 11 and 16 E6/E7 genes and EBV LMP-1 gene into primary mouse embryonic fibroblasts. The cell lines were examined for indices of transformation activity such as proliferation, induction of DNA damage, resistance to apoptosis, anchorage-independent growth, and tumor formation in nude mice. To evaluate the signaling pathways involved in transformation, NF-κB and p53 activities were analyzed. We also assessed adhesion signaling molecules associated with anchorage-independent growth such as MMP-2, paxillin and Cat-1. RESULTS: Co-expression of low-risk HPV6 E6 and EBV LMP-1 showed increased cell proliferation, elevated NF-κB activity and reduced p53 induction. Moreover, co-expression of low-risk HPV6 E6 and EBV LMP-1 induced DNA damage, escaped from apoptosis under genotoxic condition and suppression of DNA damage response (DDR). Co-expression of low-risk HPV11 E6/E7 and EBV LMP-1 demonstrated similar results. However, it led to no malignant characteristics such as anchorage-independent growth, invasiveness and tumor formation in nude mice. Compared with the cells co-expressing high-risk HPV16 E6 and EBV LMP-1 that induce transformation, co-expression of low-risk HPV6 E6 and EBV LMP-1 was associated with low MMP-2, paxillin and Cat-1 expression. CONCLUSIONS: The co-expression of low-risk HPV E6/E7 and EBV LMP-1 does not induce malignant transformation, but it allows accumulation of somatic mutations secondary to increased DNA damage and suppression of DDR. Thus, double infection of low-risk HPV and EBV could lead to precancerous lesions.