Association Of Human Papillomavirus Research Articles

P53 polymorphism and association of human papillomavirus in oral submucous fibrosis and oral squamous cell carcinoma: A case-control study.

Introduction:The tumor-suppressor p53 protein is inactivated by the human papillomavirus (HPV) E6 oncoprotein, causing polymorphism of the p53 at codon 72 of exon either proline (Pro) or arginine (Arg). Specific allele predisposition has been reported in the literature. The association between the p53 allele and HPV types has been reported. We analyzed the association between p53 polymorphism at codon 72 and HPV 16 and 18 genotypes in control, oral submucous fibrosis (OSF) and oral squamous cell carcinoma (OSCC).Materials and Methods:Of the total 90 cases, biopsy tissues of all groups (30 cases of OSF, OSCC and control each) were collected to extract DNA. Polymerase chain reaction was used to detect HPV 16 and 18 and alleles of codon 72 in p53 were evaluated in all the samples.Results:In control, OSF and OSCC samples showed the presence HPV 63.3%, 33.3% and 60%, respectively. In OSF, HPV 16 and 18 was detected in four and four cases, respectively, whereas in OSCC, HPV 16 and 18 was detected in ten and nine cases, respectively. In all three groups, predominantly, Arg/Arg protein was present followed by Pro/Pro and Arg/Pro. Among the control, Arg/Arg type protein was frequently seen followed by Arg/Pro, Pro/Pro in the presence of HPV. OSF and OSCC were associated homologous genes in the presence of HPV.Conclusion:The definite association between p53 codon 72, polymorphism and HPV 16 and 18 was seen in OSCC with low frequency in OSF. Frequency of homozygous genotype is at high risk in the presence of HPV 16 and 18 in developing OSCC.

Data Set for the Reporting of Oral Cavity Carcinomas: Explanations and Recommendations of the Guidelines From the International Collaboration of Cancer Reporting.

The International Collaboration on Cancer Reporting is a nonprofit organization whose goal is to develop evidence-based, internationally agreed-upon standardized data sets for each cancer site for use throughout the world. Providing global standardization of pathology tumor classification, staging, and other reporting elements will lead to the objective of improved patient management and enhanced epidemiologic research. Carcinomas of the oral cavity continue to represent a significant oncologic management burden, especially as changes in alcohol and tobacco use on a global scale contribute to tumor development. Separation of oral cavity carcinomas from oropharyngeal tumors is also important, as management and outcome are quite different when human papillomavirus association is taken into consideration. Topics such as tumor thickness versus depth of invasion, pattern of invasive front, extent and size of perineural invasion, and margin assessment all contribute to accurate classification and staging of tumors. This review focuses on the data set developed for Carcinomas of the Oral Cavity Histopathology Reporting Guide, with discussion of the key elements developed for inclusion.

Genetic variability and oncogenic risk association of human papillomavirus type 58 E6 and E7 genes in Taizhou area, China

It is well recognized that the association of human papillomavirus (HPV) and cervical carcinogenesis is based on the presence of HPV DNA sequence. The E6 and E7 oncoproteins encoded by high-risk HPV types play a key role in carcinogenesis. HPV58 type accounts for a larger share of cervical disease in China, whereas data on HPV58 genetic variability in China is limited. We aimed to evaluate the diversity of HPV58 genetic variants by sequencing the entire E6 and E7 genes. Phylogenetic trees were constructed by Maximum likelihood method by MEGA 5.05 software. In this study, the overall HPV infection rate was 22.6% (2891/12780) in Southeast China and the prevalence of HPV58 infection rate was 2.6% (335/12780). 26 nucleotides substitutions were observed in E6 and E7 genes with 10 novel substitutions and 17 non-synonymous substitutions. We obtained 25 distinct variation patterns which the accession GenBank numbers as MH348918-MH348942. All of HPV58 variants belong to lineage A, while no lineage B, C and D were detected in Taizhou area, Southeast China. The sublineage A1, A2, and A3 variants were found in 136 (68.3%), 39 (19.6%), and 24 (12.1%) of HPV58 isolates, respectively. The sublineage A3 variants with T20I/G63S substitutions at E7 oncoprotein carried a significantly higher risk for high-grade cervical intraepithelial neoplasia (CIN2 or worse, CIN2+) when compared with other HPV58 variants (odds ratio = 4.41, P < 0.05). Nevertheless, there was no association between HPV58 (sub) lineages and cervical lesions. These data provide the critical characteristics of HPV58 variants to assist further investigation of carcinogenic association and the development of next generation vaccines and diagnostic assays in China.

Molecular and genetic profile of head and neck squamous cell carcinoma

To determine the molecular pathways of head and neck squamous cell carcinoma (HNSCC) tumorogenesis there are held a great amount of investigations. New therapeutic models for HNSCC are discussed considering genetic and biochemical specifications and taking in account significant scientific strategies. Dividing HNSCC into 2 large groups in accordance to human papilloma virus (HPV) association with different survival rates is a great achievement of the last decades in carcinogenesis researching and treatment of HNSCC. It is well known that chemical carcinogens are the main cause of HPV-negative tumors development. HPV-positive HNSCC is associated with E6 and E7 HPV proteins. The results of whole exome sequencing of HNSCC are of the great interest. Molecular expression profile of Rb-E2F/p53 were diff erent in HPV-positive and HPV-negative tumors. The phosphorylated pRb and p16 proteins analysis showed low pRb and high p16 levels in HPV-positive tumors in contrast to HPV-negative samples due to the HPV E7 ability to degrade Rb. P16 expression was higher in HPV-positive tumors, so it is immunohystochemical marker of HPV-positive status. The p53 expression pattern is determined also to identify its mechanism of degradation in HPV-positive tumors. Due to carcinogenic HPV ability by inactivation of cell cycle regulators р53 and pRb with the help of E6 and E7 oncoproteins, mutations of TP 53 shouldn’t play leading role in HPV-induced tomorogenity. Nevertheless, there are controversial data concerning HPV-positive tumors that part of them gain p53-mutations at the same time having integrated HPV-genome. The p53 expression in HPV-positive samples was the same as if in the absence of HPV.

A report of human papilloma virus-16 associated vaginal carcinoma after thirty-two years of successful radiation therapy for cervical cancer.

Once the recommended 5-year recurrence-free follow-up is achieved for cervical cancers regular annual pelvic examination is mandatory. The main aim of presenting this short report is to emphasize the difficulties in the collection and interpretation of cytology samples from stenosed cervix or vault after pelvic irradiation. Radiotherapy can induce changes in the cellular morphology which may persist for many years. A 64-year old post-menopausal lady who had received radiation therapy 32years back for cervical carcinoma stage IIb presented to the Gynecology outpatient department with vaginal spotting. Even though the patient was under regular follow-up for the initial 2years, she was lost to further follow-ups. The patient was symptom-free except for one episode of spotting in August 2016 and the histopathological examination of the vault smear had ruled out malignancy. However, 1month later she again presented with spotting and pelvic examination revealed a warty growth at the lateral vaginal wall. The tissue excision biopsy was tested positive for HPV-16 DNA and the histopathology confirmed vaginal squamous cell carcinoma. The association of human papilloma virus (HPV) in cervical cancers was well established and these patients manifest a higher risk of HPV-induced vaginal cancers. HPV DNA testing during follow-up may facilitate early recognition of HPV-related lower genital tract cancers.

Diagnostic Algorithmic Proposal Based on Comprehensive Immunohistochemical Evaluation of 297 Invasive Endocervical Adenocarcinomas.

The International Endocervical Adenocarcinoma Criteria and Classification was developed to separate endocervical adenocarcinomas (ECAs) into 2 main categories on the basis of morphology such as human papilloma virus-associated (HPVA) and non-human papilloma virus-associated adenocarcinomas. We aimed to improve the diagnostic accuracy of International Endocervical Adenocarcinoma Criteria and Classification by performing a comprehensive immunohistochemical evaluation and constructing objective immunohistochemical-based algorithms for the classification of these tumors. Tissue microarrays were constructed from 297 of 409 cases used to develop the original classification. Immunostains included p16, p53, estrogen receptor (ER), progesterone receptor, androgen receptor, Vimentin, CK7, CK20, HER2, HIK1083, MUC6, CA-IX, SATB2, HNF-1beta, napsin A, PAX8, CDX2, GATA3, p63, p40, and TTF-1. High-risk human papilloma virus (HR-HPV) was detected by in situ hybridization (ISH) using probes against E6 and E7 mRNA expressed in 18 different virus types. Vimentin, ER, and progesterone receptor were expressed in a significant minority of ECAs, mostly HPVAs, limiting their use in differential diagnosis of endometrioid carcinoma when unaccompanied by HPV-ISH or p16. HR-HPV ISH had superior sensitivity, specificity, and negative and positive predictive values compared with p16, as published previously. HNF-1beta did not have the anticipated discriminatory power for clear cell carcinoma, nor did MUC6 or CA-IX for gastric-type carcinoma. HNF-1beta and napsin A were variably expressed in clear cell carcinoma, with HNF-1beta demonstrating less specificity, as it was ubiquitously expressed in gastric-type carcinoma and in the majority of HPV-associated mucinous (predominantly intestinal-type and invasive ECA resembling stratified mucin-producing intraepithelial lesion [iSMILE]) and usual-type carcinomas. HIK1083 was expressed in nearly half of gastric-type carcinomas, but not in the vast majority of other subtypes. GATA3 was positive in 10% of usual-type adenocarcinomas and in single examples of other subtypes. Rare gastric-type and HPVA mucinous carcinomas displayed HER2 overexpression. Androgen receptor was positive in 6% of usual-type adenocarcinomas. Aberrant p53 expression was found in only 3.6% of usual-type HPVA carcinomas, but it was more prevalent in mucinous (intestinal type and iSMILE) HPVAs and non-human papilloma virus-associates (particularly in gastric-type carcinoma, >50% of cases). The following diagnostic classification algorithms were developed with the above data. Carcinomas without overt cytoplasmic mucin (endometrioid, usual-type endocervical, clear cell, and mesonephric carcinomas) can be subclassified using HR-HPV ISH, ER, and GATA3, whereas carcinomas with easily appreciated cytoplasmic mucin (endometrioid carcinoma with mucinous features, HPVA mucinous, and gastric-type carcinomas) can be subclassified with HR-HPV ISH and ER.

Association of Human Papilloma Virus 16 & 18 and H. mole

Association of Human Papilloma Virus 16 & 18 and H. mole

A comparative meta-genomic analysis of HPV strains: A step towards the design, synthesis and characterization of noval quenazoline derivative for antiviral activity

Epigenetic characterization studies have clearly shown that the association of genital Human Papilloma Virus (HPV) with cervical cancer is strong, independent of other risk factors, and consistent in several countries. Even though all the strains of Human Papilloma Virus can cause cancer, the high-risk strains can cause severe cancer in a human. The E6 and E7 protein are responsible for the carcinogenic property of HPV. Among these two proteins, the HPV E7 protein plays a major role in the viral life cycle by allowing the virus to replicate in differentiating epithelial cells. All the strains of HPV are variants (High risk and low risk). A computational analysis study is done to find which low-risk strain is showing most similarity with the high risk there by predicting that this low-risk strain can be converted to high-risk if a mutation occurs in future. Through mutation, a normal strain will get converted to low-risk and a low-risk to high-risk. So the mutations are important and it can affect the viruses to a greater extent because of their smaller size. In order to inhibit the expression of Type 11 low-risk strain a noval suppressor molecule is synthesized and characterized using UV, FTIR and NMR spectrometry. The suppressor molecule is a quinazoline derivative, as it can act as an anti-cancer agent to inhibit the expression of the E7 protein in Type 11 strain. The efficiency of binding of type 11 E7 protein with quinazoline derivative is calculated through docking studies using G-Score (Schrodinger). Thus proposing this noval suppressor molecule can be lead against cervical cancer caused by HPV Type 11 strain after further in-vitro and in vivo characterization.

Medical Student Knowledge of Human Papillomavirus–Positive Head and Neck Cancer

This survey examines knowledge of the association of human papillomavirus and head and neck cancer among students at 10 New York State medical schools.

Prevalence and association of human papillomavirus, Epstein-Barr virus and Merkel Cell polyomavirus with neoplastic esophageal lesions in northern Iran.

Background:Studies concerning on esophageal squamous cell carcinoma (ESCC) etiological factors have been done for several decades, however, results reported from various investigations were not consistent. The present investigation aimed to explore the presence of 3 oncogenic viruses, human papilloma virus (HPV), Epstein-Barr virus (EBV) and Merkel cell polyomavirus (MCPyV) in the neoplastic and non- neoplastic esophageal lesions collected from Mazandaran, a high risk area of Iran.Methods:In total, 168 esophageal specimens (100 with ESCC confirmed diagnosis and 68 without esophageal malignancy) were analyzed for HPV, EBV and MCPyV by Real Time PCR.Results: HPV DNA was detected in 27 out of the 100 neoplastic esophageal lesions (27.0%) and 28 out of the 68 samples from non-neoplastic group (41.2%). EBV DNA was detected in esophageal specimens of 10 out of the 100 neoplastic cases (10%) and 3 out of the 68 samples in non- neoplastic group (4.4%). MCPyV DNA was detected in esophageal specimens of 30 out of the 100 neoplastic cases (30.0%) and 24 out of the 68 samples in non- neoplastic group (35.3%). There was no statistically significant difference in HPV (p=0.066), EBV (p=0.143) and MCPyV (p=0.471) DNA positivity between neoplastic and non-neoplastic groups.Conclusions: This study showed that HPV, EBV and MCPyV can be detected in both neoplastic and non-neoplastic esophageal tissues and weakens the hypothesis of the pathogenic role of these viruses in esophageal malignant transformation.

Detection of Human Papilloma Virus and Risk Factors among Patients with Head and Neck Squamous Cell Carcinoma Attending a Tertiary Referral Centre in South India

Background:Head and Neck Squamous Cell Carcinomas (HNSCC) is the sixth most common cancer globally. In India, on an average 25-30% of all cancer cases affect the head and neck. The etiological factors associated with HNSCC are tobacco, alcohol and environmental carcinogens. However there are few cases, where there are no obvious risk factors involved. In western counties, there are many reports of human papilloma virus (HPV) association with HNSCC. Hence, we conducted a study to determine the role of HPV infection and risk factors among patients with HNSCC.Materials and Methods:A prospective, cross-sectional study was conducted in a tertiary referral centre from January 2014 to March 2016. 88 patients were enrolled in the study. Socio- demographic, behavioural data, site and subsite involvement, histopathology, staging and treatment were documented. Polymerase chain reaction (PCR) was performed to detect the presence of HPV DNA using consensus primers MY 09/11 and GP5+/GP6+ and further the samples were subjected to PCR for detecting HPV type 16 and 18.Results:The study included 88 participants with HNSCC. 57 had oral and oropharyngeal squamous cell carcinoma, 11 with laryngeal malignancy and 20 involving hypopharynx. Among the participants buccal mucosa (n=22) was the most common subsite involved, majority (50%) had moderately differentiated squamous cell carcinoma and 53.4% presented in stage IV. 2 (2.6%) cases were positive for HPV consensus and both were positive for HPV 16, one case each in larynx and hypopharynx. There was statistical significance in the association between betel nut chewing, cigarette smoking and alcohol intake as risk factors in the carcinogenesis of HNSCC.Conclusion:In our setting in South India, HPV does not play a major role in the carcinogenesis of HNSCC but betel nut chewing, tobacco exposure and alcohol consumption remain major risk factors for HNSCC.

Clinicopathological profile, diagnosis and treatment of skin cancers at a tertiary care center: a retrospective study

Background: Majority of skin cancers are basal cell carcinoma, Squamous cell carcinoma and Malignant melanoma which account for more than 95% of total skin malignancies. There is an increase in incidence in India over some 10 years of period. This study was done for analysing clinicopathological profile of skin malignancies and association of human papilloma virus (HPV) in skin malignancies in Himalayan Institute of Medical Sciences (HIMS, Uttarakhand, India.Methods: It was a retrospective study done on 101 patients having malignant skin lesions attending the Department of Surgery at HIMS from October 2005 to October 2008 and given their consent.Results: Out of 101 patients, 68 had squamous cell carcinoma, 21 had basal cell carcinoma and 10 had malignant melanoma, prevalence is high in men of lower socioeconomic status (M:F) 1.9:1. The mean age was 54.50 years. Most of the patients were laborers, farmers and factory workers. Ulcers and ulceroproliferative growth were common mode of presentation. Most commonly associated risk factor was exposure to sunlight, the commonest location of skin cancer was face and scalp. Wide local excision was the commonest done procedure with closure of primary defect by SSG, fasciocutaneous or cutaneous flaps. No HPV association was seen.Conclusions: Skin cancers are quite common and their incidence has increased in last few decades, in this study we found that skin cancer were more common in males of lower socioeconomic status, probable cause was increased sun exposure and chemical exposure, in respect to females. Cancer could manifest in many forms but ulcers quite common, Squamous cell carcinoma outnumbered basal cell carcinoma, Wide local excision with skin grafts was main stay of treatment.

Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer

Background:Upfront surgery is a valuable treatment option for oropharyngeal squamous cell carcinoma (OPSCC) and risk stratification is emerging for treatment de-escalation in human papillomavirus (HPV)-related OPSCC. Available prognostic models are either based on selected, mainly non-surgically treated cohorts. Therefore, we investigated unselected OPSCC treated with predominantly upfront surgery.Methods:All patients diagnosed with OPSCC and treated with curative intent between 2000 and 2009 (n=359) were included. HPV association was determined by HPV-DNA detection and p16INK4a immunohistochemistry. Predictors with significant impact on overall survival (OS) in univariate analysis were included in recursive partitioning analysis.Results:Risk models generated from non-surgically treated patients showed low discrimination in our cohort. A new model developed for unselected patients predominantly treated with upfront surgery separates low-, intermediate- and high-risk patients with significant differences in 5-year OS (86%, 53% and 19%, P<0.001, respectively). HPV status is the most important parameter followed by T-stage in HPV-related and performance status in HPV-negative OPSCC. HPV status and ECOG remained important parameters in risk models for patients treated with or without surgery.Conclusions:Regardless of treatment strategies, HPV status is the strongest predictor of survival in unselected OPSCC patients. The proposed risk models are suitable to discriminate risk groups in unselected OPSCC patients treated with upfront surgery, which has substantial impact for design and interpretation of de-escalation trials.

Associations of Human Papillomavirus (HPV) genotypes with high-grade cervical neoplasia (CIN2+) in a cohort of women living with HIV in Burkina Faso and South Africa.

ObjectiveTo describe associations of high-risk human papillomavirus (HR-HPV) with high-grade cervical intraepithelial neoplasia (CIN2+) in women living with HIV (WLHIV) in Burkina Faso (BF) and South Africa (SA).MethodsProspective cohort of WLHIV attending HIV outpatient clinics and treatment centres. Recruitment was stratified by ART status. Cervical HPV genotyping using INNO-LiPA and histological assessment of 4-quadrant cervical biopsies at enrolment and 16 months later.ResultsAmong women with CIN2+ at baseline, the prevalence of any HR-HPV genotypes included in the bi/quadrivalent (HPV16/18) or nonavalent (HPV16/18/31/35/45/52/58) HPV vaccines ranged from 37% to 90%. HPV58 was most strongly associated with CIN2+ (aOR = 5.40, 95%CI: 2.77–10.53). At 16-months follow-up, persistence of any HR-HPV was strongly associated with incident CIN2+ (aOR = 7.90, 95%CI: 3.11–20.07), as was persistence of HPV16/18 (aOR = 5.25, 95%CI: 2.14–12.91) and the additional HR types in the nonavalent vaccine (aOR = 3.23, 95%CI: 1.23–8.54).ConclusionHR-HPV persistence is very common among African WLHIV and is linked to incident CIN2+. HPV vaccines could prevent between 37–90% of CIN2+ among African WLHIV.

Study of association and molecular analysis of human papillomavirus in breast cancer of Indian patients: Clinical and prognostic implication.

ObjectivesHuman papillomavirus (HPV) causes tumors primarily Cervical cancer. Recently, inconsistent reports came up in Breast cancer (BC) too. In India, despite treatment 70,218 BC patients die each year. So, we explored the association of HPV, if any, with BC prognosis in Indian pre-therapeutic (PT) and Neo-adjuvant chemotherapy (NACT) patients with subsequent analysis of HPV profile.MethodsHPV prevalence was checked and analysis of physical status, copy number, genome variation, promoter methylation and expression (mRNA and protein) of the prevalent subtype was done.ResultsHigh prevalence of HPV was observed in both PT (64.0%) and NACT (71.0%) cases with significant association with younger (20–45 yrs) PT patients. Interestingly, HPV infection was significantly increased from adjacent normal breast (9.5%, 2/21), fibro adenomas (30%, 3/10) to tumors (64.8%, 203/313) samples. In both PT and NACT cases, HPV16 was the most prevalent subtype (69.0%) followed by HPV18 and HPV33. Survival analysis illustrated hrHPV infected PT patients had worst prognosis. So, detailed analysis of HPV16 profile was done which showed Europian-G350 as the most frequent HPV16 variant along with high rate of integration. Moreover, low copy number and hyper-methylation of P97 early promoter were concordant with low HPV16 E6 and E7 mRNA and protein expression. Notably, four novel variations (KT020838, KT020840, KT020841 and KT020839) in the LCR region and two (KT020836 and KT020837) in the E6 region were identified for the first time along with two novel E6^E7*I (KU199314) and E6^E7*II (KU199315) fusion transcript variants.ConclusionThus, significant association of hrHPV with prognosis of Indian BC patients led to additional investigation of HPV16 profile. Outcomes indicated a plausible role of HPV in Indian BC patients.

Association of High Risk Human Papillomavirus and Breast cancer: A UK based Study

Infection by human papillomaviruses (HPVs) has been implicated in the aetiology of a variety of cancers. Studies evaluating the presence of HPVs in breast cancer (BC) have generated considerable controversy. To date, most studies have focused on the presence of viral DNA in BC; however there are important gaps in evidencing the role of HPV persistence in the invasiveness of BC. While these studies have been conducted in several countries, none, on the presence and biological activity of high risk (HR) HPV in BC has been done in the UK. Hence, we aimed to investigate these gaps by screening a total of 110 fresh breast tissue specimens from UK patients for the presence of twelve HR-HPV types DNA using PCR and Sanger sequencing. Samples positive for HPV-DNA were screened for viral oncoprotein expression using western blot and dot blot. Data obtained showed the presence of HR-HPVs in 42% of breast tissues of which the viral activity was only confirmed in a number of invasive carcinomas (5/26). This finding, the first to report in the UK, suggests that the selective expression of viral oncoprotein in invasive cases may propose a role for HR-HPVs in the development of some types of BC.

Pathologic Markers in Surgically Treated HPV-Associated Oropharyngeal Cancer: Retrospective Study, Systematic Review, and Meta-analysis.

Human papillomavirus-associated (HPV) oropharyngeal cancer is a unique clinical entity whose incidence is increasing. It is controversial whether traditional pathologic markers of aggressive head and neck cancer also apply in surgically treated HPV-associated disease. Retrospective study, systematic review, and meta-analysis Data Sources: PubMed and Cochrane review. PubMed and Cochrane review were searched for published articles on surgically treated HPV-associated oropharyngeal cancer. Eligible studies were included in a meta-analysis of survival using several clinicopathologic markers as predictors. Surgically treated HPV-positive oropharyngeal cancer patients at our institution were studied retrospectively and added to the meta-analysis. Eight published reports, plus our retrospective series, were included in the meta-analysis. This showed significant impact on event-free survival for T stage, nodal number, perineural invasion, and lymphovascular invasion (all P < .05) but not for N stage extracapsular extension ( P = ns). While many traditional clinico-pathologic markers of aggressive disease in head and neck cancer also impact survival in surgically treated HPV-associated oropharyngeal cancer, extracapsular extension may be less important.

Association of Human Papillomavirus 16 E2 with Rad50-Interacting Protein 1 Enhances Viral DNA Replication.

ABSTRACTRad50-interacting protein 1 (Rint1) associates with the DNA damage response protein Rad50 during the transition from the S phase to the G2/M phase and functions in radiation-induced G2 checkpoint control. It has also been demonstrated that Rint1 is essential in vesicle trafficking from the Golgi apparatus to the endoplasmic reticulum (ER) through an interaction with Zeste-White 10 (ZW10). We have isolated a novel interaction between Rint1 and the human papillomavirus 16 (HPV16) transcription and replication factor E2. E2 binds to Rint1 within its ZW10 interaction domain, and we show that in the absence of E2, Rint1 is localized to the ER and associates with ZW10. E2 expression results in a disruption of the Rint1-ZW10 interaction and an accumulation of nuclear Rint1, coincident with a significant reduction in vesicle movement from the ER to the Golgi apparatus. Interestingly, nuclear Rint1 and members of the Mre11/Rad50/Nbs1 (MRN) complex were found in distinct E2 nuclear foci, which peaked during mid-S phase, indicating that the recruitment of Rint1 to E2 foci within the nucleus may also result in the recruitment of this DNA damage-sensing protein complex. We show that exogenous Rint1 expression enhances E2-dependent virus replication. Conversely, the overexpression of a truncated Rint1 protein that retains the E2 binding domain but not the Rad50 binding domain acts as a dominant negative inhibitor of E2-dependent HPV replication. Put together, these experiments demonstrate that the interaction between Rint1 and E2 has an important function in HPV replication.IMPORTANCE HPV infections are an important driver of many epithelial cancers, including those within the anogenital and oropharyngeal tracts. The HPV life cycle is tightly regulated and intimately linked to the differentiation of the epithelial cells that it infects. HPV replication factories formed in the nucleus are locations where viral DNA is copied to support virus persistence and amplification of infection. The recruitment of specific cellular protein complexes to these factories aids efficient and controlled viral replication. We have identified a novel HPV-host interaction that functions in the cellular response to DNA damage and cell cycle control. We show that the HPV E2 protein targets Rad50-interacting protein 1 (Rint1) to facilitate virus genome replication. These findings add to our understanding of how HPV replicates and the host cell pathways that are targeted by HPV to support virus replication. Understanding these pathways will allow further research into novel inhibitors of HPV genome replication.

Human Papillomavirus in Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinomas (HNSCCs) are the most common cancers in India. Association, clinical presentations, and pathology of human papillomavirus (HPV) infection in 50 HNSCC patients were assessed and compared with 50 patients having benign head and neck lesions in a prospective study. Punch biopsy from the lesion in all the patients was used for confirmation of the diagnosis and HPV DNA isolation by PCR assay. All HNSCC patients had poor oral hygiene, and 28% of them had uncommon sexual practices. Eighty-eight percent of patients were smokers while 68% were alcoholic. The association of HPV in HNSCC was 42% as compared to 8% in benign lesions (p = 0.001). Twenty-one of 50 HNSCC patients tested positive for HPV, of which 20 were positive for HPV 16 and 1 was positive for HPV 18 whereas only 4 out of 50 patients with benign lesions were HPV positive, all of which were positive for HPV 16. Out of 21 HPV-positive HNSCC patients, 9 (42%) had a history of uncommon sexual practices as compared to 5 out of 29 (17.2%) in HPV-negative HNSCC patients. It is concluded that the association of HPV in HNSCC was significantly high and a significant number of HPV-positive HNSCC patients were associated with uncommon sexual practices as compared to HPV-negative HNSCC patients. A larger study is recommended to further confirm this high association of HPV in malignancy and defining a role of vaccination program for the primary prevention of HNSCC.

Different Association of Human Papillomavirus 16 Variants with Early and Late Presentation of Cervical Cancer.

The median age of cervical cancer (CC) presentation coincides with the mean age of menopause presentation (49 years) in Mexico. Here, we investigated the association between different HPV16 variants and early (≤ 49 years) or delayed (≥ 50 years) CC presentation. We conducted a case-case study that included 462 CCs, 386 squamous cell carcinomas (SCC), 63 adenocarcinomas (ACC), and 13 additional cell types. Variants were identified by PCR and DNA sequencing. The risk conferred by each variant for developing CC earlier than 50 years was analyzed using a univariate logistic regression model considering old-aged patients (≥ 50 years) and non-HPV16 cases as the reference variables. Overall, the frequency of HPV16 was 50.9%, and the only identified variants were the European A1/2 (31.2%) and the Asian-American D2 (10.8%), and D3 (8.9%). D2 was mainly associated with ≤ 49-year-old patients (15.9%); A1/2 was uniformly distributed between the two age groups (~31%), whereas D3 increased with age to a frequency of 11.8% in the older group. Only the D2 variant conferred a 3.3-fold increase in the risk of developing CC before 50 years of age (OR = 3.3, 95% CI = 1.7–6.6, p < 0.001) in relation with non-HPV16 cases. Remarkably, this risk was higher for ACC (OR = 6.0, 95% CI = 1.1–33, p < 0.05) than for SCC (OR = 2.8, 95% CI = 1.3–5.9, p < 0.01). Interestingly, when analyzing only the HPV16-positive CC, D2 increases (OR = 2.5, 95% CI = 1.2–5, p < 0.05) and D3 decreases (OR = 0.45, 95% CI 0.2–0.9, p < 0.05) the risk to develop CC before 50 years old in relation with A1/2 variant. These results indicated that D2 variant is associated with early and D3 with delayed CC presentation, whereas A1/2 variant was uniformly distributed between the two age groups.