Precision design of an HLA-I-targeted multiepitope vaccine against human papillomavirus 16 oncoproteins E6/E7: integrated immunoinformatic and immunogenicity profiling.

Oral squamous cell carcinoma positive for p16/human papilloma virus in post allogeneic stem cell transplantation: 2 cases and review of the literature

BackgroundLittle is known about the natural history of human papillomavirus (HPV) infection in Asian women.MethodsA follow-up study was conducted, with exfoliated cervicovaginal cells self-collected from, and questionnaires administered to 197 female students, aged 17–26 years, who had been already examined one and half years before. The presence of 25 HPV types was evaluated by a polymerase chain reaction-based assay.ResultsThe acquisition of new infection for any HPV type among 171 female students at risk who were negative at baseline, 60% of whom had remained as virgins, was 17.5% (95% confidence interval [CI]: 11.8–23.2). Among individual types, HPV16, 18 and 35 showed the highest rate of new infection. Women who had had first sexual intercourse (OR = 2.9; 95% CI: 1.0–8.8), or had changed sexual partners (OR = 2.9; 95% CI: 0.9–9.3) during the follow-up period showed a higher risk of new HPV infection than women who had remained virgins since baseline. The rate of new infection also tended to be higher in those who started, or continued smoking during the follow-up period, than in nonsmokers. Clearance of HPV infections since baseline examination was 80.6% (95% CI: 67.6–93.5), and did not differ between high-risk and low-risk HPV types or between single- and multiple-type infections.ConclusionThis study shows that the acquisition of new HPV infection among young women in the Republic of Korea is high and also the clearance is frequent. Self-collection of cervicovaginal cells is applicable to follow-up studies that include virgins.

Rate of human papillomavirus clearance after treatment of cervical intraepithelial neoplasia

The relationship between circumcision and the acquisition and clearance of human papillomavirus (HPV) infection was examined in a cohort of 357 men followed up at 2-month intervals for an average of 431 days. There were no differences in HPV acquisition by circumcision status. Clearance of HPV infection, including infection with oncogenic types, was slower in the glans/coronal sulcus of the penis of uncircumcised men than circumcised men. The median duration of HPV infection of the glans/coronal sulcus was significantly longer in uncircumcised men (154 days) than circumcised men (91 days) (P=.04). Circumcision may protect against HPV-associated disease by enhancing the resolution of infection.

Impact of HPV vaccination on the incidence and clearance of HPV infections in sexually active young women.

Little is known about the natural history of human papillomavirus (HPV) infection in male virgins. This study estimated the incidence and clearance of genital HPV infection and the factors associated with these measures among men who denied at baseline ever having penetrative sex. A cohort of 4123 men residing in Brazil, Mexico, and the United States were followed every 6 months for up to 10 visits. Genital exfoliated cells were collected and genotyped for 36 HPV types. Eighty-seven men were classified as virgins and included for analysis. Cox proportional hazards models identified factors associated with the incidence and clearance of genital HPV infection. The incidence rates for any HPV infection among virgins who did and those who did not initiate sex during follow-up were 26.2 and 14.6 cases/1000 person-months, respectively. After penetrative sex initiation, 45.5% of men acquired HPV within 24 months. Younger age, current smoking, no recent female sex partners, and prevalent HPV infection were associated with high-risk HPV clearance. Virgins who did not initiate sex during follow-up still acquired HPV infection, possibly through nonpenetrative sexual contact. Further prospective cohort studies are needed to better understand factors associated with HPV acquisition and clearance in male virgins and recent nonvirgins.

Persistence and clearance of human papillomavirus infection: a prospective cohort study

Our understanding of factors associated with acquisition and clearance of human papillomavirus (HPV) in men has been limited. This study sought to determine factors associated with those aspects of HPV infection in a cohort of US men. A total of 285 men aged 18-44 years were monitored every 6 months for approximately 18 months. Risk-factor information was obtained at each visit by use of a self-administered questionnaire. A continuous-time 2-state Markov model was applied. Lifetime number of sex partners reported at enrollment was the most significant risk factor for acquisition of all types of HPV. Men reporting >16 lifetime sex partners were at significantly elevated risk of any HPV infection (adjusted hazard ratio [AHR], 2.8 [95% confidence interval {CI}, 1.1-7.1]), oncogenic HPV infection (AHR, 9.6 [95% CI, 2.4-37.8]), and nononcogenic HPV infection (AHR, 3.6 [95% CI, 1.3-9.9]), compared with those reporting 0-4 partners. Circumcised men were 3 and 6 times more likely to clear infection with any and oncogenic HPV types, respectively. In addition, having had >16 lifetime sex partners was associated with greater likelihood of clearance of oncogenic HPV infection (AHR, 4.9 [95% CI, 1.2-19.8]). The key factor associated with acquisition of HPV was lifetime number of sex partners, whereas circumcision was the most significant determinant for clearance of any HPV infection and oncogenic HPV infection.

We investigated the use of mice transgenic for human leucocyte antigen (HLA) A*0201 antigen-binding domains to test vaccines composed of defined HLA A*0201-restricted cytotoxic T-lymphocyte (CTL) epitopes of human papillomavirus (HPV) type 16 E7 oncoprotein. HPV is detected in >90% of cervical carcinomas. HPV16 E7 oncoprotein transforms cells of the uterine cervix and functions as a tumour-associated antigen to which immunotherapeutic strategies may be directed. We report that although the HLA A*0201 E7 epitope peptides function both to prime for E7 CTL responses, and to sensitize target cells for E7-directed CTL killing in situations where antigen processing is not required, the epitopes are not processed out of either endogenously expressed or immunization-introduced E7, by the mouse antigen-processing and presentation machinery. Thus (1) CTL induced by HLA A*0201 peptide immunization killed E7 peptide-pulsed target cells, but did not kill target cells expressing whole E7; (2) immunization with whole E7 protein did not elicit CTL directed to HLA A*0201-restricted E7 CTL epitopes; (3) HLA A*0201-restricted CTL epitopes expressed in the context of a DNA polytope vaccine did not activate E7-specific T cells either in 'conventional' HLA A*0201 transgenic (A2.1Kb) mice, or in HHD transgenic mice in which expression of endogenous H-2 class 1 is precluded; and (4) HLA A*0201 E7 peptide epitope immunization was incapable of preventing the growth of an HLA A*0201- and E7-expressing tumour. There are generic implications for the universal applicability of HLA-class 1 transgenic mice for studies of human CTL epitope presentation in murine models of human infectious disease where recognition of endogenously processed antigen is necessary. There are also specific implications for the use of HLA A2 transgenic mice for the development of E7-based therapeutic vaccines for cervical cancer.

Despite many years of rigorous evaluation of a variety of interventions, HIV incidence rates in parts of Africa remain unacceptably high. A recent review identified 37 randomized controlled trials testing interventions to reduce HIV incidence.1 Except for 3 randomized controlled trials of male circumcision2‐4 and 1 trial of syndromic treatment of sexually transmitted diseases,5 and, recently, 1 trial of a vaginal microbicide,6 no significant reductions in HIV incidence were observed. In some trials of vaginal microbicides, trial participants in the active treatment arm actually had increased HIV incidence rates.7 Trials with candidate vaccines have been equally disappointing.8 A recently completed trial of a prime-boost strategy conducted in Thailand showed statistically significant, but limited, protection against HIV.9 Nevertheless, even vaccine optimists think that a preventive HIV vaccine is many years away. Sexually transmitted infections (STIs) were identified as important cofactors for HIV transmission early in the epidemic.10,11 Many prospective observational studies showed that the presence of ulcerative and nonulcerative STIs increased the likelihood of HIV transmission.10,11 Several interventions were based on this observation including mass treatment with antibiotics,12 improved syndromic management of STIs,5,13 and herpes simplex virus (HSV)-2 suppressive treatment.14 Null findings of these interventions should be interpreted with caution. Failure to show an effect does not necessarily mean that the STI is not causally associated with HIV. As Barnabas and Wasserheit highlight,15 the stage of the HIV epidemic in which an intervention trial is conducted may significantly influence observed efficacy. Another possible reason for the failure of these trials to demonstrate efficacy is that the intervention may not have adequately controlled the STI or its biologic effects.

Human papillomavirus (HPV) infection is the principal cause of invasive cervical cancer. There is some evidence that male circumcision (MC) may protect against HPV infection and related disease in both men and women. The purpose of this study was to conduct a systematic review of the literature to assess the association between MC and genital HPV infection indicators including genital warts. A systematic search of Medline was conducted to identify all relevant studies from February 1971 to August 2010. Effect estimates were included in random effects models. A total of 21 studies with 8046 circumcised and 6336 uncircumcised men were included in the meta-analysis. MC was associated with a statistically significant reduced odds of genital HPV prevalence (odds ratio = 0.57, 95% confidence interval: 0.42-0.77). This association was also observed for genital high-risk HPV prevalence in 2 randomized controlled trials (odds ratio = 0.67, 95% confidence interval: 0.54-0.82). No associations were found between MC and genital HPV acquisition of new infections, genital HPV clearance, or genital warts. This meta-analysis shows a robust inverse association between MC and genital HPV prevalence in men. However, more studies are needed to adequately assess the effect of MC on the acquisition and clearance of HPV infections. MC could be considered as an additional one-time preventative intervention likely to reduce the burden of HPV-related diseases both in men and women, particularly among those countries in which HPV vaccination programs and cervical screening are not available.

Immunity to oncogenic human papillomaviruses

The role of human leukocyte antigen E and G in HIV infection

Increased Sensitivity of Radiated Murine Cervical Cancer Tumors to E7 Subunit Vaccine–driven CTL-mediated Killing Induces Synergistic Anti-tumor Activity

HPV represents a large group of double stranded DNA viruses that are highly involved with different types of human cancers. This synopsis describes the complexities surrounding HPV virology, classifications, and genomic variation, especially focusing on high-risk strains such as HPV16 and HPV18, the main causative factors for cervical cancers. The International Committee on Taxonomy of Viruses specifies more than 200 HPV types each associated with a respective disease and indicated in Table 1. HPV spread is mostly due to direct skin-to-skin contact between individuals’ sex organs causing infections on the mucous membrane and keratinized epithelial cells. Although majority of the infections are asymptomatic, some chronic HRHPV infections may progress into cancers because of oncoproteins E6 and E7. The high-risk variants of HPV lead to cervical, anal, and oropharyngeal cancers whereas the low-risk types cause harmless genital warts. While integrating HPV DNA into the host genome, orchestrated by oncoproteins E6 and E7 disrupts the cell regulatory mechanism; this leads to abnormal control over cell multiplication–one of the major elements of the process that develops to HPV induced cancer. A classic case is cervical cancer that has been extensively investigated as one of the highly documented HPV associated malignancies. Pap smears and HPV DNA tests are among the screening means that lower the incidents and deaths associated with cervical cancers. HPV-associated cancers of the head and neck, anus, penis, vulva, and vagina all show a characteristic profile in terms of the pathogen aetiology and risks involved. HPV-related head and neck cancers affect non-smokers and show good response to standard therapies. HPV poses increased anal cancer risk for immunocompromised individuals highlighting the complexity of interdependence of immunity and cancer development. Penile cancer results from poor hygiene and non-circumcision. Vulvar and virginal cancer mostly affects women, and the risk factors involve HPV infection and smoking. Therefore, various types of multidisciplinary approach that may include surgeries, radiotherapy, and chemotherapy are necessary to ensure proper treatment. Certain cancers are strongly associated with some high-risk HPV genotypes, such as HPV-16 and HPV-18; thus, vaccination is important. HPV infection outcomes are determined by the immune response as well as clearance of HPV infection. Screening and immunological understanding for early detection of HPV related health risks is fundamental. However, this encompassing review highlights the multi-dimensional impact of HPV encompassing virology of HPV, cancer specific presentation of HPV and control including prevention of HPV infection, screening, and research on cancer attributable by HPV and strategies towards mitigation of this global health problem.