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Genotypes of the human papillomavirus: Relevance to Indian field trials of the vaccine
Abstract
Highly effective HPV vaccines are likely to become available for use in India shortly. The availability and validation of the vaccines to prevent oncogenic HPV infection associated lesions from progressing to cancer has clearly offered a cost effective long-term strategy to reduce the cervical cancer burden, particularly for developing countries where effective screening programmes are not available. The enthusiasm for these new vaccines duly justified, are we in reality targeting the actual delinquent by prompting these vaccines in India? The answer would be no as we may not be essentially implementing a rational fool-proof vaccine program which will aid in preventing HPV-related diseases, for the simple reason that there is a lack of understanding about the underlying HPV types responsible for cervical cancer in India. Field trials involving large populations form a major part of continued analysis in understanding any disease and India is still short of such a trial as far as cervical cancer is concerned. Conducting such studies, might also act as prevention programs that will save lives and improve public health in a substantive manner.
... HPV 35 (5.6%), HPV 45 (5.6%), HPV 52 (2.8%), HPV 58 (2.8%). 13 The number of multiple genotypes of HPV detected in our study was slightly less than what was seen in a study by Lai et al. In their study multiple type of HPV were seen in 9.6% of patients. ...
NTRODUCTION: Several studies have demonstrated world over that 99 per cent of cervical tumors are having the presence of human papillomaviruses (HPV). 1 More than 111 genotypes of HPV have been described, but only about 30 of them are associated with ano-genital cancer. HPV 16/18 is estimated to account for more than 80 per cent of invasive cervical cancer. 2 Altogether HPV 16, 18, 45, 31,33, 35, 52, 58 are responsible for about 90 per cent of all cervical cancers worldwide. 3 HPV has been correlated with treatment response in some studies with varying results. Increased mortality is seen in HPV negative patient as compared to HPV positive patients. 4 HPV 18, multiple HPV types have a more aggressive phenotype, higher recurrence rate and a worse prognosis than those with HPV 16. 5,6 This study was conducted to find out the association of HPV infection in patients with carcinoma cervix and the variation in response to treatment with different genotypes of HPV. ABSTRACT: Aim and Objective-Cervix cancer is the third most commonly diagnosed cancer and the fourth leading cause of cancer death in females worldwide. Some 99 per cent of cervical cancer cases are linked to genital infection with human papillomaviruses (HPVs). The clinicopathological parameters and response to radiotherapy varies with the genotypes of HPV. This study was aimed at association of HPV with cervical carcinoma and to evaluate the correlation of different HPV genotypes with parameters such as histological type, age at onset, clinical stage and response to radiotherapy in diagnosed cases of carcinoma cervix.HPV DNA was detected by Real time PCR technique in the cervical smears of 50 patients of FIGO stage-IIA to IIIB. Materials and Method-Association was then estimated between HPV genotypes and various clinicopathological parameters. External beam radiation with concurrent chemotherapy followed by intracavitary brachytherapy was delivered to all patients. Response to radiotherapy was then assessed according to different HPV genotypes. Chi Square test of significance was used for all the calculations.A total of 50 patients were analyzed. Results-HPV DNA sequences were detected in 84% of the specimens. Among HPV positive samples, HPV 16 and HPV 18 were found in 67% and 21 % of the samples respectively.Poorer response to radiotherapy was observed in the patients negative for HPV genotype or positive for HPV-18 genotype. No correlation was seen between HPV genotype and other clinicopathological parameters like age, stage, histopathological type. Conclusion-These data suggest that the HPV type present in cervical carcinoma is related to clinical behavior and response to radiotherapy.
... Over 130 have had their genomes completely sequenced and of these 15 have been designated `high-risk` due to their propensity to provoke transformation of the epithelial cells they have infected. 13 Of these, two 'high risk' types -HPV 16 and 18 -have been definitively implicated in the development of cervical cancer. ...
The prevalence of oropharyngeal squamous cell carcinoma (OPSCC) has increased to epidemic proportions in Europe and the United States of America over the last three decades. Most of this increase has been attributed to an exponential rise in the incidence of Human Papilloma Virus (HPV) associated OPSCC: HPV-16 being the most common genotype. HPV associated tumours constitute a discrete disease entity, with non-smoking, non-heavy drinking patients presenting at an earlier age than their counterparts presenting with HPV negative tumours. This article highlights evidence of this increased incidence and describes the genetic make-up of HPV. In addition, we explain the mechanisms underlying the ability of HPV to transform normal epithelial cells into cancer cells. Finally, we describe the current methods employed to detect HPV infection and conclude by highlighting a diagnostic algorithm which has been proposed as a pragmatic strategy to maximise the detection of HPV infection in oropharyngeal tumour tissue.
... As India is a diverse country with different ethinicity, communities, variations in epidemiological factors could contribute to differences from the current study. The contribution of such factors to variations in the prevalence of different types of HPV has been previously reported [16,17]. ...
The prevalence of human papillomavirus (HPV) infection in India is high. HPV infection is known to cause cervical cancer and has also been implicated in the pathogenesis of retinoblastoma (RB), a common intraocular malignant tumor of childhood which can be familial or sporadic. Despite the high incidence of RB in India, its familial form is rare. Hence this study was undertaken to investigate whether high-risk HPV types 16 and 18 are involved in the development of RB.
Formalin fixed paraffin embedded RB tissues (n = 76) including prospective cases with corresponding maternal cervical smears (n = 10) were analyzed for the presence of HPV DNA sequences. Expression of the cell cycle regulatory proteins viz; p105, p107, p30, p16, E2F-1, E2F-4, and MiB-1 was studied by immunohistochemistry (IHC) (n = 34).
A total of 53 out of 76 (69.7%) cases were positive for HPV, of these 3 cases were positive for HPV-16, 23 for HPV-18, and 27 for both HPV-16 and -18. Of the prospective cases (n = 10) studied, five cases along with the corresponding maternal cervical cytology smear had identical HPV status. HPV-16 positive tumors were classified as well differentiated (P = 0.013). Nuclear expression of pRB2/p130 showed significant association with HPV-16 infection (P = 0.04) or dual infection of HPV-16/-18 (P = 0.02).
Our study lends support to the hypothesis that infection of HPV-16/-18 may play an important role in the development of nonfamilial form of RB in children in India.
Introduction
Cervical cancer is the second leading cause of deaths due to cancer, among Indian women. Persistent infection of high-risk genotypes of human papillomavirus (HPV) is the leading cause of cervical cancer. The aim of the study was to estimate the incidence of HPV 16 and 18 infections in cervical cancer patients from Jabalpur, Madhya Pradesh, India.
Materials and Methods
In this hospital-based study, cervical biopsy samples, received from tertiary healthcare hospital, were subjected to molecular tests for HPV 16 and HPV 18. The p53 polymorphism at the 72 position was studied by PCR. The clinical and sociodemographic information of the patients was analyzed using SPSS 20.
Result
A total of 87 cervical carcinoma tissues were analyzed by type-specific PCR for its presence. Forty-five (51.7%) were infected with HPV 16, and 27 (31%) had HPV 18. Coinfection of HPV 16 and HPV 18 was detected in 15 (17.2%) patients. The overall HPV incidence was 65.5% (n = 57). Arginine (Arg) homozygosity dominance was not significant among cervical carcinoma patients. Illiteracy was significantly associated with HPV incidence.
Conclusion
The findings indicate HPV 16 and HPV 18 are the major causes of cervical carcinoma in Central India. HPV 16 was more prominent infection than HPV 18. Arg homozygosity at the 72 position in p53 gene was not associated with cervical carcinoma. A community-based study will be useful to establish the prevalence of HPV, which will help in interventions such as vaccination in the area.
Cervical cancer is the second commonest cause of cancer among women. According to the World Health Organization (WHO) data, in 2006 there were 1.4 million women who were suffering from cervical cancer and 80% of deaths among them were of women from developing countries. Genital infection with Human Papilloma Virus (HPV) is one of the major etiological factors for developing cervical cancers in almost all countries (World Health Organization, 2005). Papilloma viruses were first identified, cloned and sequenced from cervical tumor specimens and were subsequently established as important causative agents for the development of cervical cancer. Differences in prevalence rates are observed worldwide. Infection is more common in sexually active young women of 18-30 years and a reduction in acquisition of infection is observed after 30 years. The situation of Cervical cancer in Sri Lanka is identified as the second most common cancer among women in Sri Lanka and approximately 7.74 million women are included in the risk category. It is reported that nearly 850 die from cervical cancer each year.
Cervical cancer is the second commonest cause of cancer among women. According to the World Health Organization (WHO) data, in 2006 there were 1.4 million women who were suffering from cervical cancer and 80% of deaths among them were of women from developing countries. Genital infection with Human Papilloma Virus (HPV) is one of the major etiological factors for developing cervical cancers in almost all countries (World Health Organization, 2005).Papilloma viruses were first identified, cloned and sequenced from cervical tumor specimens and were subsequently established as important causative agents for the development of cervical cancer. Differences in prevalence rates are observed worldwide. Infection is more common in sexually active young women of 18-30 years and a reduction in acquisition of infection is observed after 30 years.
Human papillomavirus (HPV) is a virus from the papillomavirus family that is capable of infecting humans. Some types of HPVs cause warts, while others can lead to cancers of the cervix, vulva, vagina, penis, oropharynx and anus. High-risk human papillomavirus (hr HPV) has been detected
in almost all cervical squamous cell carcinomas and adenocarcinomas. All patients examined by colposcopy. Cervical swab is routinely done and patients are screened with both HPV DNA by Real Time Polimerase Chain Reaction (RT PCR) testing and Pap testing. Pictures obtained by colposcopy were
examined by indirect Bi-Digital O-Ring Test (BDORT) by using reference control substance (RCS): HPV 16, HPV 18, and Integrin α5 β1. BDORT was developed by Prof. Omura Y. of New York and received U. S. patent in 1993. For detection of HPV DNA we used RT PCR and standard Qiagen method
which detect 18 types (16,18,31,33,35,39,45,51,52,56,58,59,68, 6,11,42,43,44) of HPV from smear. From 63 patients where is BDORT indicated presence of HPV, in 49 pateints (77,8%) RT PCR confirmed presence of HPV. From 63 patients in 54 patients (85,7%), we detected, by colposcopic exam, some
kind of lesions associated with HPV infection. Results obtained by RT PCR: one type (1/18) of DNA HPV in 25 patients (51,02%), 2 types (2/18) in 15 patients (30,61%) and 3 types (3/18) in 9 patients (18,37%). Although BDORT results usually have higher sensitivity and detection rate is much
higher, it can be used together with RT PCR in detection of HPV and cervical lesions associated with HPV infection.
Infection with human papilloma virus (HPV) is the main cause of cervical cancer, but the risk associated with the various HPV types has not been adequately assessed.
We pooled data from 11 case-control studies from nine countries involving 1918 women with histologically confirmed squamous-cell cervical cancer and 1928 control women. A common protocol and questionnaire were used. Information on risk factors was obtained by personal interviews, and cervical cells were collected for detection of HPV DNA and typing in a central laboratory by polymerase-chain-reaction-based assays (with MY09/MY11 and GP5+/6+ primers).
HPV DNA was detected in 1739 of the 1918 patients with cervical cancer (90.7 percent) and in 259 of the 1928 control women (13.4 percent). With the GP5+/6+ primer, HPV DNA was detected in 96.6 percent of the patients and 15.6 percent of the controls. The most common HPV types in patients, in descending order of frequency, were types 16, 18, 45, 31, 33, 52, 58, and 35. Among control women, types 16, 18, 45, 31, 6, 58, 35, and 33 were the most common. For studies using the GP5+/6+ primer, the pooled odds ratio for cervical cancer associated with the presence of any HPV was 158.2 (95 percent confidence interval, 113.4 to 220.6). The odds ratios were over 45 for the most common and least common HPV types. Fifteen HPV types were classified as high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82); 3 were classified as probable high-risk types (26, 53, and 66); and 12 were classified as low-risk types (6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, and CP6108). There was good agreement between our epidemiologic classification and the classification based on phylogenetic grouping.
In addition to HPV types 16 and 18, types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82 should be considered carcinogenic, or high-risk, types, and types 26, 53, and 66 should be considered probably carcinogenic.
Most cancers of the uterine cervix are squamous cell carcinomas. Although the incidence of such carcinomas of the uterine cervix has declined over time, that of cervical adenocarcinoma has risen in recent years. The extent to which human papillomavirus (HPV) infection and cofactors may explain this differential trend is unclear.
We pooled data from eight case-control studies of cervical cancer that were conducted on three continents. A total of 167 case patients with invasive cervical adenocarcinoma (112 with adenocarcinoma and 55 with adenosquamous carcinoma) and 1881 hospital-based control subjects were included. HPV DNA was analyzed in cervical specimens with the GP5+/6+ general primer system followed by type-specific hybridization for 33 HPV genotypes. Blood samples were analyzed for chlamydial and herpes simplex virus 2 (HSV-2) serology. Multivariable unconditional logistic regression modeling was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs). All tests of statistical significance were two-sided.
The adjusted overall odds ratio for cervical adenocarcinoma in HPV-positive women compared with HPV-negative women was 81.3 (95% CI = 42.0 to 157.1). HPV 16 and HPV 18 were the two most commonly detected HPV types in case patients and control subjects. These two types were present in 82% of the patients. Cofactors that showed clear statistically significant positive associations with cervical adenocarcinoma overall and among HPV-positive women included never schooling, poor hygiene, sexual behavior-related variables, long-term use of hormonal contraception, high parity, and HSV-2 seropositivity. Parity had a weaker association with adenocarcinoma and only among HPV-positive women. Use of an intrauterine device (IUD) had a statistically significant inverse association with risk of adenocarcinoma (for ever use of an IUD compared with never use, OR = .41 [95% CI = 0.18 to 0.93]). Smoking and chlamydial seropositivity were not associated with disease.
HPV appears to be the key risk factor for cervical adenocarcinoma. HPV testing in primary screening using current mixtures of HPV types and HPV vaccination against main HPV types should reduce the incidence of this cancer worldwide.
Vaccination against the most common oncogenic human papillomavirus (HPV) types, HPV-16 and HPV-18, could prevent development of up to 70% of cervical cancers worldwide. We did a randomised, double-blind, controlled trial to assess the efficacy, safety, and immunogenicity of a bivalent HPV-16/18 L1 virus-like particle vaccine for the prevention of incident and persistent infection with these two virus types, associated cervical cytological abnormalities, and precancerous lesions.
We randomised 1113 women between 15-25 years of age to receive three doses of either the vaccine formulated with AS04 adjuvant or placebo on a 0 month, 1 month, and 6 month schedule in North America and Brazil. Women were assessed for HPV infection by cervical cytology and self-obtained cervicovaginal samples for up to 27 months, and for vaccine safety and immunogenicity.
In the according-to-protocol analyses, vaccine efficacy was 91.6% (95% CI 64.5-98.0) against incident infection and 100% against persistent infection (47.0-100) with HPV-16/18. In the intention-to-treat analyses, vaccine efficacy was 95.1% (63.5-99.3) against persistent cervical infection with HPV-16/18 and 92.9% (70.0-98.3) against cytological abnormalities associated with HPV-16/18 infection. The vaccine was generally safe, well tolerated, and highly immunogenic.
The bivalent HPV vaccine was efficacious in prevention of incident and persistent cervical infections with HPV-16 and HPV-18, and associated cytological abnormalities and lesions. Vaccination against such infections could substantially reduce incidence of cervical cancer.
The temporal relationship between primary genital human papillomavirus (HPV) infections and the induction of antibodies against viral antigens has not been established. In order to address this question we studied a cohort of 110 women and 48 men with multiple heterosexual partners, who were followed for 220 person-years during which they made 583 visits to the sexually transmitted diseases clinic of the Amsterdam Public Health Service. At each visit spatula or brush samples from multiple anogenital and oral sites were collected for HPV DNA analysis by PCR. Serum samples were also collected and analysed for serological reactivity to peptides derived from the L1, L2 and E2 regions of HPV types 6, 16 and 18 as well as to bovine papillomavirus and HPV-16 virus-like particles. Seroconversions for at least three antigens were found among 16/158 patients. Of these, 10/16 were HPV-positive and in 5/16 cases seroconversions occurred concomitantly with the detection of HPV DNA. Analysis of participants who were HPV-negative at entry, but became HPV DNA-positive during follow-up revealed that antibodies against several HPV antigens were regularly induced at the time of a new HPV infection, in particular the IgG responses against HPV-16 virus-like particles and against the HPV-16 E2-derived peptide 245. Whereas the responses induced among the women with new HPV-16 infection tended to continuously increase, the responses among the men with any type of new HPV infection were mostly transient and disappeared during follow-up. In conclusion, we find that antibody responses to multiple viral antigens are often induced following the detection of genital HPV infection, that the type-specificity of the response is limited and that transient responses are common.
Infection of mucosal epithelium by papillomaviruses is responsible for the induction of genital and oral warts and plays a critical role in the development of human cervical and oropharyngeal cancer. We have employed a canine model to develop a systemic vaccine that completely protects against experimentally induced oral mucosal papillomas. The major capsid protein, L1, of canine oral papillomavirus (COPV) was expressed in Sf9 insect cells in native conformation. L1 protein, which self-assembled into virus-like particles, was purified on CsCl gradients and injected intradermally into the foot pad of beagles. Vaccinated animals developed circulating antibodies against COPV and became completely resistant to experimental challenge with COPV. Successful immunization was strictly dependent upon native L1 protein conformation and L1 type. Partial protection was achieved with as little as 0.125 ng of L1 protein, and adjuvants appeared useful for prolonging the host immune response. Serum immunoglobulins passively transferred from COPV L1-immunized beagles to naive beagles conferred protection from experimental infection with COPV. Our results indicate the feasibility of developing a human vaccine to prevent mucosal papillomas, which can progress to malignancy.
We report a system for generating infectious papillomaviruses in vitro that facilitates the analysis of papillomavirus assembly, infectivity, and serologic relatedness. Cultured hamster BPHE-1 cells harboring autonomously replicating bovine papillomavirus type 1 (BPV1) genomes were infected with recombinant Semliki Forest viruses that express the structural proteins of BPV1. When plated on C127 cells, extracts from cells expressing L1 and L2 together induced numerous transformed foci that could be specifically prevented by BPV neutralizing antibodies, demonstrating that BPV infection was responsible for the focal transformation. Extracts from BPHE-1 cells expressing L1 or L2 separately were not infectious. Although Semliki Forest virus-expressed L1 self-assembled into virus-like particles (VLPs), viral DNA was detected in particles only when L2 was coexpressed with L1, indicating that genome encapsidation requires L2. Expression of human papillomavirus type 16 (HPV16) L1 and L2 together in BPHE-1 cells also yielded infectious virus. These pseudotyped virions were neutralized by antiserum to HPV16 VLPs derived from European (114/K) or African (Z-1194) HPV16 variants but not by antisera to BPV VLPs, to a poorly assembling mutant HPV16 L1 protein, or to VLPs of closely related genital HPV types. Extracts from BPHE-1 cells coexpressing BPV L1 and HPV16 L2 or HPV16 L1 and BPV L2 were not infectious. We conclude that (i) mouse C127 cells express the cell surface receptor for HPV16 and are able to uncoat HPV16 capsids; (ii) if a papillomavirus DNA packaging signal exists, then it is conserved between the BPV and HPV16 genomes; (iii) functional L1-L2 interaction exhibits type specificity; and (iv) protection by HPV virus-like particle vaccines is likely to be type specific.
Two cocktails of digoxigenin-labeled human papillomavirus (HPV) type-specific oligonucleotide probes and an enzyme immunoassay (EIA) were used as a basis to developed a group-specific detection method for 14 high-risk (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) and 6 low-risk (types 6, 11, 40, 42, 43, and 44) HPVs, following a general primer GP5+/bioGP6(+)-mediated PCR. The sensitivity of this high-risk/low-risk (HR/LR) HPV PCR-EIA ranged from 10 to 200 HPV copies, depending on the HPV type. Comparison of HR/LR HPV PCR-EIA with radioactive Southern blot hybridization using a general probe on the same PCR products derived from 417 cytomorphologically abnormal cervical scrapings resulted in an overall agreement of 96% between the two methods. Complete concordance between group-specific HR/LR detection and individual typing results for both single and multiple infections indicate the strong specificity of this HR/LR HPV PCR-EIA. Multiple infections could be predicted by comparing PCR-EIA optical density values of the cocktail probes with one of the individual oligonucleotide probes. This novel HR/LR PCR-EIA allows accurate and rapid identification of high-risk and low-risk HPV types in cervical scrapings and will facilitate HPV detection in HPV mass-screening programs.
We have determined that three type-specific and conformationally dependent monoclonal antibodies, H16.E70, H16.U4, and H16.V5, neutralize pseudotype human papillomavirus type 16 (HPV16) virions in vitro. H16.U4 and H16.V5 neutralized pseudotype virions derived from the German HPV16 variant 114K and the Zairian variant Z-1194 with equal efficiency. In contrast, neutralization of Z-1194 pseudotype virions by H16.E70 was two orders of magnitude weaker than neutralization of 114K pseudotype virions. This difference correlated with enzyme-linked immunosorbent assay reactivity of H16.E70 to L1 virus-like particles of the two variants. A substitution at residue 282 of L1 was responsible for this differential reactivity, suggesting that this residue constitutes part of the H16.E70 epitope.
Genital human papillomavirus (HPV) infection is highly prevalent in sexually active young women. However, precise risk factors for HPV infection and its incidence and duration are not well known.
We followed 608 college women at six-month intervals for three years. At each visit, we collected information about lifestyle and sexual behavior and obtained cervicovaginal-lavage samples for the detection of HPV DNA by polymerase chain reaction and Southern blot hybridization. Pap smears were obtained annually.
The cumulative 36-month incidence of HPV infection was 43 percent (95 percent confidence interval, 36 to 49 percent). An increased risk of HPV infection was significantly associated with younger age, Hispanic ethnicity, black race, an increased number of vaginal-sex partners, high frequencies of vaginal sex and alcohol consumption, anal sex, and certain characteristics of partners (regular partners having an increased number of lifetime partners and not being in school). The median duration of new infections was 8 months (95 percent confidence interval, 7 to 10 months). The persistence of HPV for > or =6 months was related to older age, types of HPV associated with cervical cancer, and infection with multiple types of HPV but not with smoking. The risk of an abnormal Pap smear increased with persistent HPV infection, particularly with high-risk types (relative risk, 37.2; 95 percent confidence interval, 14.6 to 94.8).
The incidence of HPV infection in sexually active young college women is high. The short duration of most HPV infections in these women suggests that the associated cervical dysplasia should be managed conservatively.
The long control region (LCR) and the E2 protein of human papillomaviruses (HPV) are the most important viral factors regulating transcription of the viral oncogenes E6 and E7. Sequence variation within these genomic regions may have an impact on the oncogenic potential of the virus. Sequence variation in the LCR and in the E2 gene of human papillomavirus type 16 (HPV-16) isolates originating from cervical cancer patients from East Hungary was studied. In 30 samples, sequencing and/or single-strand conformation polymorphism analysis revealed variants belonging to the European variant lineage of HPV-16. These variants differed from the reference European clone only slightly in their E2 and LCR sequences. Three samples represented variants belonging to the Asian-American group. These differed from the published reference sequence at several positions in the LCR and E2 regions. Compared to the reference clone, the LCR clones of the European isolates showed very similar transcriptional activities, while that of an Asian-American isolate had approximately 1.7-fold increased activity. Most of the increased activity of the Asian-American isolate could be ascribed to nucleotide changes found at the 3' end of the LCR (nt 7660-7890). The transcriptional transactivation potentials of the HPV-16 E2 isolates differed only slightly from each other, and the differences seemed to be independent of the taxonomic position of the isolates.
Persistent infection with human papillomavirus type 16 (HPV-16) is strongly associated with the development of cervical cancer. Neutralizing epitopes present on the major coat protein, L1, have not been well characterized, although three neutralizing monoclonal antibodies (MAbs) had been identified by using HPV-16 pseudovirions (R. B. Roden et al., J. Virol. 71:6247-6252, 1997). Here, two of these MAbs (H16.V5 and H16.E70) were demonstrated to neutralize authentic HPV-16 in vitro, while the third (H16.U4) did not. Binding studies were conducted with the three MAbs and virus-like particles (VLPs) composed of the reference L1 sequence (114K) and three variant L1 sequences: Rochester-1k (derived from viral stock DNA), GU-1 (derived from cervical biopsy DNA), and GU-2 (derived from biopsy DNA, but containing some sequence changes likely to be artifactual). While all three MAbs bound to 114K and Rochester-1k VLPs, GU-1 VLPs were not recognized by H16.E70, and both H16.E70 and H16.V5 failed to bind to GU-2 VLPs. Site-directed mutagenesis was used to replace disparate amino acids in the GU-2 L1 with those found in the 114K L1. Alteration of the amino acid at position 50, from L to F, completely restored H16.V5 binding and partially restored H16.E70 binding, while complete restoration of H16.E70 binding occurred with GU-2 VLPs containing both L50F and T266A alterations. Immunization of mice with L1 variant VLPs revealed that GU-2 VLPs were poorly immunogenic. The L50F mutant of GU-2 L1, in which the H16.V5 epitope was restored, elicited HPV-16 antibody responses comparable to those obtained with 114K VLPs. These results demonstrate the importance of the H16.V5 epitope in the generation of potent HPV-16 neutralizing antibody responses.
Conjugate vaccines have reduced the incidence of invasive disease caused by Haemophilus influenzae, type b (Hib), in industrialized countries and may be highly effective against Streptococcus pneumoniae. However, the serotype specificity of these vaccines has led to concern that their use may increase carriage of and disease from serotypes not included in the vaccine. Replacement has not occurred with the use of Hib vaccines but has occurred in trials of pneumococcal vaccines. Mathematical models can be used to elucidate these contrasting outcomes, predict the conditions under which serotype replacement is likely, interpret the results of conjugate vaccine trials, design trials that will better detect serotype replacement (if it occurs), and suggest factors to consider in choosing the serotype composition of vaccines.
Human papillomavirus (HPV) can be detected by amplification of viral DNA. A novel PCR primer set generating a short PCR fragment (SPF PCR) was used for amplification of a fragment of only 65 bp from the L1 region and permitted ultrasensitive detection of a broad spectrum of HPV genotypes. The intra- and intertypic sequence variations of the 22-bp interprimer region of this amplimer were studied. Among 238 HPV sequences from GenBank and clinical specimens, HPV genotypes were correctly identified based on the 22-bp sequence in 232 cases (97.2%). Genotype-specific probes for HPV genotypes 6, 11, 16, 18, 31, 33 to 35, 39, 40, 42 to 45, 51 to 54, 56, 58, 59, 66, 68, 70, and 74 were selected, and a reverse hybridization line probe assay (LiPA) (the INNO-LiPA HPV prototype research assay) was developed. This LiPA permits the use of amplimers generated by the SPF as well as the MY 09/11 primers. The assay was evaluated with a total of 1, 354 clinical specimens, comprising cervical scrapes (classifications ranging from normal cytology to severe dyskaryosis) and formalin-fixed, paraffin-embedded cervical carcinoma samples. LiPA results were highly concordant with sequence analysis of the SPF amplimer, genotype-specific PCR, and sequence analysis of amplimers generated by MY 09/11 primers. The sensitivity of the SPF primers was higher than that of the GP5(+)/6(+) primers over a broad range of HPV types, especially when multiple HPV genotypes were present. In conclusion, the SPF LiPA method allows extremely sensitive detection of HPV DNA as well as reliable identification of HPV genotypes in both cervical smears and paraffin-embedded materials.
Hybrid Capture II (HC-II) is a commercial human papillomavirus (HPV) detection test designed to detect 18 HPV types divided into high-risk and low-risk groups. We have tested 1647 scrapes from 1518 unselected women attending routine cytological screening by this assay for the detection of histologically proven high-grade lesions. The reliability of this test was also evaluated on 117 fresh cone biopsy samples. HPV DNA has been detected in 400 scrapes (24.3%), 296 containing a high-risk HPV (18.0%). All the smears evocative of high-grade lesions were positive for high-risk HPV, and high-risk HPV were detected in all the 34 cases presenting a histologically proven high-grade lesion and in 68 (97.1%) of the 70 cone biopsy samples showing a high-grade lesion or an invasive carcinoma. Thus, the sensitivity was superior to the sensitivity of cytology (85.3%). Nevertheless, the quantitative approach provided by the HC-II assay for the assessment of the viral load could not clearly distinguish among cases with or without high-grade lesions. Thus this assay is recommended for the screening of high-grade lesions on a large scale, in association with classic cytology.
Human papillomavirus (HPV)—16 causes about half the cases of cervical cancer worldwide and is the focus of HPV vaccine development
efforts. Systematic data are lacking as to whether the prevention of HPV-16 could affect the equilibrium of infection with
other HPV types and thus alter the predicted impact of vaccination on the occurrence of cervical neoplasia. Therefore, the
associations of HPV-16 detection with subsequent acquisition of other HPV types and with the persistence of concomitantly
detected HPV types were examined prospectively among 1124 initially cytologically normal women. Preexisting HPV-16 was generally
associated with an increased risk for subsequent acquisition of other types. HPV-16 did not affect the persistence of concomitant
infections, regardless of type. These findings suggest that the prevention or removal of HPV-16 is not likely to promote the
risk of infection with other types, a theoretical concern with current vaccination efforts.
Two cocktails of digoxigenin-labeled human papillomavirus (HPV) type-specific oligonucleotide probes and an enzyme immunoassay (EIA) were used as a basis to developed a group-specific detection method for 14 high-risk (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) and 6 low-risk (types 6, 11, 40, 42, 43, and 44) HPVs, following a general primer GP5+/bioGP6(+)-mediated PCR. The sensitivity of this high-risk/low-risk (HR/LR) HPV PCR-EIA ranged from 10 to 200 HPV copies, depending on the HPV type. Comparison of HR/LR HPV PCR-EIA with radioactive Southern blot hybridization using a general probe on the same PCR products derived from 417 cytomorphologically abnormal cervical scrapings resulted in an overall agreement of 96% between the two methods. Complete concordance between group-specific HR/LR detection and individual typing results for both single and multiple infections indicate the strong specificity of this HR/LR HPV PCR-EIA. Multiple infections could be predicted by comparing PCR-EIA optical density values of the cocktail probes with one of the individual oligonucleotide probes. This novel HR/LR PCR-EIA allows accurate and rapid identification of high-risk and low-risk HPV types in cervical scrapings and will facilitate HPV detection in HPV mass-screening programs.
Viruses that belong to six different families are a significant cause for neoplasia in man and animals. Among them are the Papillomaviruses that cause uterine cervical cancer in women. Efforts to develop prophylactic vaccines against viruses that cause cancer are now a major research engagement. Vaccinology, the science of vaccines, engages the sciences of immunology and of microbiology, both relying heavily on molecular biology. Successful development of vaccines relies on extensive knowledge of immunology and vaccinology. Present efforts to develop vaccines against cervical cancer caused by Papillomaviruses are focused on use of the structural antigens L1 and L2 of the virus and on the oncoproteins E6 and E7. Work on Papillomavirus vaccines has been brilliantly conceived and executed and some of vaccines are now in clinical trial. Success may follow and Papillomavirus vaccine may join with the hepatitis B virus anti-cancer vaccine in the battle against cancers of man.
Prophylactic human papillomavirus (HPV) virus-like particle (VLP) vaccines are highly effective. The available evidence suggests that neutralising antibody is the mechanism of protection. However, despite the robust humoral response elicited by VLP vaccines, there is no immune correlate, no minimum level of antibody, or any other immune parameter, that predicts protection against infection or disease. The durability of the antibody response and the importance of antibody isotype, affinity and avidity for vaccine effectiveness are discussed. Once infection and disease are established, then cellular immune responses are essential to kill infected cells. These are complex processes and understanding the local mucosal immune response is a prerequisite for the rational design of therapeutic HPV vaccines. This article forms part of a special supplement entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.
High-risk human papillomavirus (HPV) infection plays an important role in cervical intra-epithelial neoplasia (CIN), but HPV infection alone is not sufficient for progression to cervical cancer. Several lines of evidence suggest that cellular immune surveillance is important in the control of HPV infection and the development of CIN. The presentation to T cells of target viral peptides in the context of HLA molecules is influenced by the genetic polymorphisms of both HPV and HLA and thereby influences the host immune response and clinical outcome of HPV infection. HLA class I and II polymorphism in susceptibility for HPV 16 infection, development and progression of CIN was analyzed in a group of 118 patients participating in a prospective study of women with initial abnormal cytology. Patients were stratified according to HPV status and course of the disease. HLA-B*44 frequency was increased in the small group of patients with a lesion that showed clinical progression during follow-up [OR = 9.0 (4.6–17.5),p= 0.007]. HLA-DRB1*07 frequency was increased among HPV 16-positive patients compared with patients who were negative for all HPV types [OR = 5.9 (3.0–11.3), p= 0.02]. Our results are consistent with the immunogenetic factors associated with disease progression being different from those associated with susceptibility to HPV 16 infection. Sequencing of the HPV 16 E6 and E7 open reading frames of a subset of these patients (n = 40) showed the frequency of HPV 16 variants to be similar to other studies. However, there was no significant correlation between variant incidence and disease progression or viral persistence and no significant correlation with any HLA allele. It appears that multiple HLA types can influence HPV 16-associated cervical dysplasia but the role of HPV 16 variants in disease progression and susceptibility in relation to HLA polymorphism remains unclear. Int. J. Cancer 78:166–171, 1998.© 1998 Wiley-Liss, Inc.
Objective:
The aim of this study was to compare the age-adjusted incidence and survival for invasive adenocarcinoma and squamous cell carcinoma of the uterine cervix using population-based data.
Methods:
The SEER database was used to identify all cases of cervical cancer registered between 1973 and 1996. Stage was defined as localized, regional, or distant. Age-adjusted incidence rates were analyzed statistically using the Jonchkeere-Terpstra exact test for trends. Relative and observed survival rates, respectively, were compared using z tests and log-rank tests.
Results:
The age-adjusted incidence rates per 100,000 for all invasive cervical cancers decreased by 36.9% over 24 years [12.35 (1973-1977) vs 7.79 (1993-1996)]. Similarly, the age-adjusted incidence rates for squamous cell carcinoma declined by 41.9% [9.45 (1973-1977) vs 5.49 (1993-1996)]. In contrast, the age-adjusted incidence rates for adenocarcinoma increased by 29.1% [1.34 (1973-1977) vs 1.73 (1993-1996)]. The proportion of adenocarcinoma increased 107.4% relative to all cervical cancer, 95.2% relative to squamous cell carcinoma, and 49.3% relative to the population of women at risk [10. 8% vs 22.4% (P < 0.001), 12.4% vs 24.0% (P < 0.001), and 1.40 vs 2. 09 per 100,000 women (P < 0.001), respectively]. Observed survival rates for adenocarcinoma vs squamous cell carcinoma were poorer for regional (P = 0.04), but not localized or distant disease.
Conclusions:
Over the past 24 years, the incidence of all cervical cancer and squamous cell carcinoma has continued to decline. However, the proportion of adenocarcinoma relative to squamous cell carcinoma and to all cervical cancers has doubled, and the rate of adenocarcinoma per population at risk has also increased. These results suggest that current screening practices in the United States are insufficient to detect a significant proportion of adenocarcinoma precursor lesions.
Data on human papillomavirus (HPV) type distribution in invasive and pre-invasive cervical cancer is essential to predict the future impact of HPV16/18 vaccines and HPV-based screening tests. A meta-analyses of HPV type distribution in invasive cervical cancer (ICC) and high-grade squamous intraepithelial lesions (HSIL) identified a total of 14,595 and 7,094 cases, respectively. In ICC, HPV16 was the most common, and HPV18 the second most common, type in all continents. Combined HPV16/18 prevalence among ICC cases was slightly higher in Europe, North America and Australia (74-77%) than in Africa, Asia and South/Central America (65-70%). The next most common HPV types were the same in each continent, namely HPV31, 33, 35, 45, 52 and 58, although their relative importance differed somewhat by region. HPV18 was significantly more prevalent in adeno/adenosquamous carcinoma than in squamous cell carcinoma, with the reverse being true for HPV16, 31, 33, 52 and 58. Among HSIL cases, HPV16/18 prevalence was 52%. However, HPV 16, 18 and 45 were significantly under-represented, and other high-risk HPV types significantly over-represented in HSIL compared to ICC, suggesting differences in type-specific risks for progression. Data on HPV-typed ICC and HSIL cases were particularly scarce from large regions of Africa and Central Asia.
Background:
Epidemiologic studies have shown that the association of genital human papillomavirus (HPV) with cervical cancer is strong, independent of other risk factors, and consistent in several countries. There are more than 20 different cancer-associated HPV types, but little is known about their geographic variation.
Purpose:
Our aim was to determine whether the association between HPV infection and cervical cancer is consistent worldwide and to investigate geographic variation in the distribution of HPV types.
Methods:
More than 1000 specimens from sequential patients with invasive cervical cancer were collected and stored frozen at 32 hospitals in 22 countries. Slides from all patients were submitted for central histologic review to confirm the diagnosis and to assess histologic characteristics. We used polymerase chain reaction-based assays capable of detecting more than 25 different HPV types. A generalized linear Poisson model was fitted to the data on viral type and geographic region to assess geographic heterogeneity.
Results:
HPV DNA was detected in 93% of the tumors, with no significant variation in HPV positivity among countries. HPV 16 was present in 50% of the specimens, HPV 18 in 14%, HPV 45 in 8%, and HPV 31 in 5%. HPV 16 was the predominant type in all countries except Indonesia, where HPV 18 was more common. There was significant geographic variation in the prevalence of some less common virus types. A clustering of HPV 45 was apparent in western Africa, while HPV 39 and HPV 59 were almost entirely confined to Central and South America. In squamous cell tumors, HPV 16 predominated (51% of such specimens), but HPV 18 predominated in adenocarcinomas (56% of such tumors) and adenosquamous tumors (39% of such tumors).
Conclusions:
Our results confirm the role of genital HPVs, which are transmitted sexually, as the central etiologic factor in cervical cancer worldwide. They also suggest that most genital HPVs are associated with cancer, at least occasionally.
Implication:
The demonstration that more than 20 different genital HPV types are associated with cervical cancer has important implications for cervical cancer-prevention strategies that include the development of vaccines targeted to genital HPVs.
The majority of domestic rabbits developed invasive, metastatic, and, ultimately, lethal epidermoid carcinomas. The Shope papilloma has a restricted geographic range, mostly confined to the high plains of the western United States. SPV (Shope papilloma virus) produced papillomas with equal facility on the skins of laboratory-infected jackrabbits, snowshoe hares, domestic rabbits, and cottontails. Papillomas cannot be induced in fetal, neonatal, suckling, or adult rat skin by direct inoculation of SPV suspensions or infectious DNA. Susceptibility to SPV infection is also determined by factors related to cell phenotype. Rabbit epidermal cell transformation by SPV requires interaction with mesenchyme. Vitamin A deficiency or excess can produce striking alterations in the differentiation of epithelia of various types. SPV replication in cottontail papillomas is also modulated by phenotypic factors—namely, epidermal maturation and keratinization. Independent studies have confirmed the presence of arginase in Shope papilloma but have not supported the assertion that the enzyme is encoded by the SPV genome. The Shope papilloma-carcinoma complex is an excellent model of neoplastic progression. Papillomas that become malignant undergo a characteristic series of gross morphological changes.
Our aim was to study the phylogenetic relationships of all known papillomaviruses (PVs) and the possibility of establishing a supratype taxonomic classification based on this information. Of the many detectably homologous segments present in PV genomes, a 291-bp segment of the L1 gene is notable because it is flanked by the MY09 and MY11 consensus primers and contains highly conserved amino acid residues which simplify sequence alignment. We determined the MY09-MY11 sequences of human PV type 20 (HPV-20), HPV-21, HPV-22, HPV-23, HPV-24, HPV-36, HPV-37, HPV-38, HPV-48, HPV-50, HPV-60, HPV-70, HPV-72, HPV-73, ovine (sheep) PV, bovine PV type 3 (BPV-3), BPV-5, and BPV-6 and created a database which now encompasses HPV-1 to HPV-70, HPV-72, HPV-73, seven yet untyped HPV genomes, and 15 animal PV types. Three additional animal PVs were analyzed on the basis of other sequence data. We constructed phylogenies based on partial L1 and E6 gene sequences and distinguished five major clades that we call supergroups. One of them unites 54 genital PV types, which can be further divided into eleven groups. The second supergroup has 24 types and unites most PVs that are typically found in epidermodysplasia verruciformis patients but also includes several types typical of other cutaneous lesions, like HPV-4. The third supergroup unites the six known ungulate fibropapillomaviruses, the fourth includes the cutaneous ungulate PVs BPV-3, BPV-4, and BPV-6, and the fifth includes HPV-1, HPV-41, HPV-63, the canine oral PV, and the cottontail rabbit PV. The chaffinch PV and two rodent PVs, Micromys minutus PV and Mastomys natalensis PV, are left ungrouped because of the relative isolation of each of their lineages. Within most supergroups, groups formed on the basis of cladistic principles unite phenotypically similar PV types. We discuss the basis of our classification, the concept of the PV type, speciation, PV-host evolution, and estimates of their rates of evolution.
Epidemiologic studies have shown that the association of genital human papillomavirus (HPV) with cervical cancer is strong, independent of other risk factors, and consistent in several countries. There are more than 20 different cancer-associated HPV types, but little is known about their geographic variation.
Our aim was to determine whether the association between HPV infection and cervical cancer is consistent worldwide and to investigate geographic variation in the distribution of HPV types.
More than 1000 specimens from sequential patients with invasive cervical cancer were collected and stored frozen at 32 hospitals in 22 countries. Slides from all patients were submitted for central histologic review to confirm the diagnosis and to assess histologic characteristics. We used polymerase chain reaction-based assays capable of detecting more than 25 different HPV types. A generalized linear Poisson model was fitted to the data on viral type and geographic region to assess geographic heterogeneity.
HPV DNA was detected in 93% of the tumors, with no significant variation in HPV positivity among countries. HPV 16 was present in 50% of the specimens, HPV 18 in 14%, HPV 45 in 8%, and HPV 31 in 5%. HPV 16 was the predominant type in all countries except Indonesia, where HPV 18 was more common. There was significant geographic variation in the prevalence of some less common virus types. A clustering of HPV 45 was apparent in western Africa, while HPV 39 and HPV 59 were almost entirely confined to Central and South America. In squamous cell tumors, HPV 16 predominated (51% of such specimens), but HPV 18 predominated in adenocarcinomas (56% of such tumors) and adenosquamous tumors (39% of such tumors).
Our results confirm the role of genital HPVs, which are transmitted sexually, as the central etiologic factor in cervical cancer worldwide. They also suggest that most genital HPVs are associated with cancer, at least occasionally.
The demonstration that more than 20 different genital HPV types are associated with cervical cancer has important implications for cervical cancer-prevention strategies that include the development of vaccines targeted to genital HPVs.
Human papillomavirus (HPV) type 6 capsids were produced by recombinant vaccinia viruses and used in a capture ELISA to screen
901 human sera from three studies of genital HPVs. The highest seroprevalence was observed among subjects with recurrent genital
warts. In a population-based case-control study of genital warts, 26 (58%) of 45 women with recurrent genital warts were seropositive
compared with 19 (19%) of 101 control women with no history of genital warts (odds ratio, 6.5; 95% confidence interval, 3.0,
14.1). Among a cohort of pregnant women, 7 (88%) of 8 with recurrent warts were seropositive compared with 24 (30%) of 79
pregnant women with no such history. A significant association between seropositivity to HPV-6 capsids and the detection of
HPV 6/11 DNA from genital specimens by polymerase chain reaction was also observed. Men with genital warts were less likely
to be seropositive than were women with genital warts, and a positive association between the number of sex partners and seropositivity
was observed among only the female university students.
Human leukocyte antigen (HLA) molecules, whose biological role is in the regulation of immune responses to foreign antigens and in discrimination of self from non-self antigens, are encoded by a series of closely linked genetic loci found on chromosome 6. Although the evidence for a link between HLA and cervical cancer has been controversial, it has been recently reported that certain HLA class II haplotypes (linked class II alleles) are positively associated with invasive cervical cancer, while other class II haplotypes are negatively associated or protective. Since HLA associations between human papillomavirus type 16 (HPV16)-mediated cancer cases and non-HPV16-mediated cancer cases have been found to be different, this suggests that specific HLA class II haplotypes may influence the immune response to HPV infection and may affect the risk of acquiring invasive cervical carcinoma.
This study was conducted to determine if the same HLA class II haplotypes that are associated with invasive cervical carcinoma are also associated with cervical dysplasia (presumed precursors of invasive cervical cancer).
We have examined HLA DR-DQ haplotypes among 128 Hispanic women from New Mexico with biopsy-confirmed cervical dysplasia in a case-control study using sensitive DNA-based polymerase chain reaction amplification and sequence-specific oligonucleotide probe hybridization methods to detect the presence and type of HPV and to detect allelic polymorphism in the HLA DRB1 and DQB1 loci.
Dysplasia cases were divided into two groups for comparison to controls: severe dysplasia/carcinoma in situ (CIS), and slight/moderate dysplasia. The frequency distribution of HLA class II haplotypes among the HPV16-positive severe dysplasia/CIS cases had a statistically significant (two-tailed P < .005) difference compared with controls, whereas haplotypes among the severe dysplasia/CIS cases containing HPV types other than HPV16 did not show statistically significant frequency differences. DR-DQ haplotypes previously found to be associated with HPV16-invasive cervical carcinomas were also associated with HPV16-positive severe dysplasia/CIS. However, no statistically significant haplotype frequency difference was observed between slight/moderate dysplasia cases and controls. In addition, we noted a DQA1-DQB1 haplotype negatively associated with severe dysplasia/CIS but not with invasive cervical cancers.
Our results strongly suggest that certain HLA haplotypes confer an increased risk for severe cervical dysplasia and invasive cervical carcinoma following HPV16 infection.
Further molecular studies are needed to identify HLA alleles or haplotypes that may provide increased susceptibility to HPV-associated cervical disease.
Previous studies have demonstrated that genital infection with high-risk types of human papillomavirus (HPV), most often HPV16, is the most significant risk factor for the development of cervical cancer. However, serologic assays that have been developed to identify high-risk HPV infection have either failed to associate serum reactivity with other indicators of HPV infection or have identified only a minority of HPV-infected individuals.
Our purpose was to determine whether a specifically developed enzyme-linked immunosorbent assay (ELISA) could detect IgG anti-HPV16 virion antibodies in the sera of women who had tested positive for genital HPV16 infection by DNA-based methods.
An ELISA was developed using newly developed HPV16 virus-like particles as antigens to detect anti-HPV16 virion IgG antibodies. These particles are comprised of HPV16 structural proteins that are self-assembled in insect cells after expression by recombinant baculoviruses. The sera of 122 women, whose HPV status had been previously evaluated by nucleic acid-based methods, were tested by this ELISA.
The sera of 59% of women (32 of 54) positive for genital HPV16 DNA by polymerase chain reaction (PCR) were positive in the ELISA assay compared with sera from women who had tested negative for HPV DNA (P < .0005). In contrast, 6% of HPV DNA-negative women (two of 31) and 9% of women positive for low-risk HPV6/11 DNA (one of 11) were ELISA positive by this criterion. The sera of women who were DNA positive for two additional high-risk HPV types were evaluated; the sera of 31% of HPV18-positive (four of 13) and 38% of HPV31-positive women (five of 13) were positive in the HPV16 particle ELISA. The sera of 75% of HPV16 DNA-positive women with severe dysplasias (12 of 16) gave positive ELISA results. The sera of 67% of women (28 of 42) who tested positive for HPV16 DNA by both PCR and the less sensitive ViraType assay tested positive in the ELISA compared with 33% of women (four of 12) who were positive by PCR but negative by ViraType (P < .05).
The majority of women with cervical HPV16 infection generate an IgG antibody response to conformationally dependent epitopes of HPV16 L1 that can be detected by ELISA.
This particular ELISA, or a similar one incorporating virus-like particles of additional HPV types, may be useful in determining the natural history of high-risk HPV infection and perhaps help to identify women at risk for developing cervical cancer.
Three naturally occurring variant human papillomavirus type 16 (HPV-16) E6 proteins, which contained amino acid substitutions predominantly near the N terminus, exhibited significant differences in their abilities to abrogate keratinocyte differentiation in response to serum and calcium and to induce the degradation of p53 in vitro. One variant surpassed the reference E6 protein in its ability to abrogate keratinocyte differentiation responses, whereas another showed a reduction in this activity. Interestingly, the biological activities of the HPV-16 E6 proteins and their abilities to induce p53 degradation in vitro were directly correlated. These results demonstrate that naturally occurring variants of HPV-16 differ in biological and biochemical properties which might result in differences in pathogenicity.
The association of HLA class II DQB1 and DRB1 alleles with the development of cervical carcinoma was studied in 150 Swedish patients using PCR-based HPV and HLA typing. The association of cervical carcinoma with alleles encoding the DQ3 antigen, previously found among German and Norwegian patients, was not observed in the Swedish patients. Five DQ-DR haplotypes were indicated to be positively associated with development of cervical carcinoma in the Swedish patients. Two of these HLA associations were specific for HPV 18 infected patients, suggesting that the ability of the oncogenic HPV 18 to cause more rapid-transit tumors than other high risk HPV types may be due to a deficiency in antigen presentation by the HLA molecules encoded by carried on these haplotypes.
A review is presented of 15 years of clinical experience working with women who developed cervical cancer within a short interval after the last reported negative Papanicolaou smear. Our initial report concerned isolated cases in which women were diagnosed with invasive cervical cancer within 1 year of a reported normal Papanicolaou smear. Our second report focused on a 10-year review of the Yale-New Haven Hospital experience, during which 40 of 555 women had rapidly progressive invasive disease; 35 cases (87.5%) occurred in women younger than 40 years old and almost all of the 40 diagnosed because of persistent symptoms despite a recent normal Papanicolaou smear. Our final experience is a population-based study of all women in Connecticut who developed cervical cancer between 1985 and 1990. A total of 118 of 481 (24.5%) participants were diagnosed with cervical cancer within 3 years of their last true-negative Papanicolaou smear. Adenocarcinomas occurred in 38 cases (32.2%). These data suggest that rapidly occurring cervical cancer may be a manifestation of endocervical carcinomas that have been inadequately screened.
Genital infection with high-risk human papillomaviruses (HPV) has been etiologically linked with the development of cervical and other anogenital cancers. There is therefore a need for an effective HPV vaccine with the potential to significantly reduce the burden of more than half a million new cervical cancer cases in women worldwide each year. The L1 major capsid protein of papillomaviruses expressed in eukaryotic cells self-assembles into virus-like particles (VLP). VLP are attractive subunit vaccine candidates since they lack potentially oncogenic papillomavirus DNA and express the conformationally dependent epitopes necessary to induce high-titer neutralizing antibodies. Prophylactic VLP vaccination has achieved a high degree of protection in animal studies. Thus VLP are now considered the immunogen of choice for human vaccine trials to prevent genital HPV infection. VLP of different HPV have been developed to study the serologic relationship between HPV types. VLP-based ELISA are able to detect antibodies in human sera and are now widely used in epidemiologic studies of the natural history of HPV infection and the associated risk of developing neoplasia.
Conjugate vaccines protect vaccinated individuals against both disease from and nasopharyngeal carriage of Streptococcus pneumoniae and Haemophilus influenzae. Protection is specific to the capsular serotype(s) included in the vaccine. This specificity has raised concern that vaccination against particular ("targeted") serotypes may cause an increase in carriage of (and diseases attributable to) nontargeted serotypes. I analyzed a mathematical model designed to predict the factors affecting, and the expected extent of, such replacement in the host population. The conditions for competitive exclusion and coexistence of serotypes under mass vaccination are derived, and the equilibrium carriage of target and nontarget serotypes is determined under various ecological and epidemiological conditions. The eradication threshold for a target serotype in the presence of competing, nontarget serotypes is always lower for serotype-specific than for bivalent vaccines. In a two-serotype model, the increase in the prevalence of any single nontargeted serotype due to vaccination will not exceed the total reduction in prevalence of a targeted serotype. However, if three or more serotypes interact epidemiologically, vaccination against one type may increase carriage of a second more than it decreases carriage of the first. Carriage of a second serotype against which the vaccine offers only partial protection may initially increase and then decrease as a function of vaccine coverage. I discuss the extent to which these theoretical results can account for existing data on serotype replacement after vaccination against H. influenzae and their implications for vaccine policy.
Although it is difficult to estimate the overall prevalence of genital human papillomavirus (HPV) infection, current figures suggest that visible genital warts are present in approximately 1% of sexually active adults in the United States and that at least 15% have subclinical infection, as detected by HPV DNA assays. Genital HPV infection is thus extremely common. The highest rates of genital HPV infection are found in adults 18-28 years of age. Although risk factors for infection are difficult to assess because of the high frequency of subclinical infection, it is clear that major risk factors for acquiring genital HPV infection involve sexual behavior, particularly multiple sex partners. Other possible risk factors for acquisition of genital HPV infection include oral contraceptive use, pregnancy, and impairment of cell-mediated immunity. Strong epidemiologic and molecular data link HPV infection to cervical and other anogenital cancers. The types of HPV most commonly detected in cancers are HPV-16 and HPV-18. In summary, genital HPV infection is common among sexually active populations and causes both benign and malignant neoplasms of the genital tract.
High-risk human papillomavirus (HPV) infection plays an important role in cervical intra-epithelial neoplasia (CIN), but HPV infection alone is not sufficient for progression to cervical cancer. Several lines of evidence suggest that cellular immune surveillance is important in the control of HPV infection and the development of CIN. The presentation to T cells of target viral peptides in the context of HLA molecules is influenced by the genetic polymorphisms of both HPV and HLA and thereby influences the host immune response and clinical outcome of HPV infection. HLA class I and II polymorphism in susceptibility for HPV 16 infection, development and progression of CIN was analyzed in a group of 118 patients participating in a prospective study of women with initial abnormal cytology. Patients were stratified according to HPV status and course of the disease. HLA-B*44 frequency was increased in the small group of patients with a lesion that showed clinical progression during follow-up [OR = 9.0 (4.6-17.5), p = 0.007]. HLA-DRB1*07 frequency was increased among HPV 16-positive patients compared with patients who were negative for all HPV types [OR = 5.9 (3.0-11.3), p = 0.02]. Our results are consistent with the immunogenetic factors associated with disease progression being different from those associated with susceptibility to HPV 16 infection. Sequencing of the HPV 16 E6 and E7 open reading frames of a subset of these patients (n = 40) showed the frequency of HPV 16 variants to be similar to other studies. However, there was no significant correlation between variant incidence and disease progression or viral persistence and no significant correlation with any HLA allele. It appears that multiple HLA types can influence HPV 16-associated cervical dysplasia but the role of HPV 16 variants in disease progression and susceptibility in relation to HLA polymorphism remains unclear.
The current study was designed to elucidate risk factors associated with the development of cervical cancer during the course of routine Papanicolaou smear screening (rapid-onset cervical cancer).Study Design: Four hundred eighty-three women diagnosed with invasive cervical cancer, representing 73% of all such tumors diagnosed in Connecticut between 1985 and 1990, were studied. Papanicolaou smear screening and risk factor information was obtained by questionnaire and physician record review. Results from human papillomavirus deoxyribonucleic acid testing by polymerase chain reaction of tumor samples were available for 278 study participants. Prediagnostic Papanicolaou smear slides were reviewed for 67% of cases with a screening history. Screening history information, slide review, and questionnaire data were used to classify women as having rapid-onset cervical cancer (n = 43), possible rapid-onset cervical cancer (n = 111), or normal-onset cervical cancer (n = 329).
Compared with normal-onset cases, rapid-onset cases tended to be younger (P =.001) and were more likely to be white (P =.002), diagnosed with adenocarcinomas or adenosquamous carcinomas (P =.001), and diagnosed with early-stage disease (P =.001). Cases diagnosed as possible rapid-onset disease tended to have a profile that was intermediate to that observed for rapid-onset and normal-onset cases. Human papillomavirus deoxyribonucleic acid was detected in 75.2% of cases tested. Compared with women who tested positive for human papillomavirus type 16 or other, those positive for human papillomavirus type 18 had a relative risk for rapid-onset disease of 1.6 (95% confidence interval 0.52-4.9). No significant association was observed between type 18 and possible rapid-onset disease when possible rapid-onset cases were compared with women diagnosed with normal-onset cervical cancer (relative risk 0.67, 95% confidence interval 0.29-1.6). Oral contraceptive use, cigarette smoking, number of pregnancies, and a maternal history of cervical cancer were not significantly associated with rapid-onset disease.
Results from this study suggest that the risk factors associated with the development of rapid-onset cervical cancer are similar to those for normal-onset disease.
The proceedings of the UICC 17th International Cancer Congress, held in Rio de Janeiro in August, are now available on videotape. The following videos are available: Highlights of the Congress, Interviews with the Panels, Prostate Diseases (ICUD/UICC/WHO), Global Cancer Facts and Figures (Dr. Max Parkin), The Fatal Combination in Cancer Development: Self-Stimulation and Self-Renewal (Dr. Donald Metcalf), Viral Oncology: The HPV Story (Dr. Harald zur Hausen), Nature and Nurture (Sir Richard Doll), Metastases (Dr. Max Burger), Pain Management in Cancer (Dr. Charles Cleeland), Behavioral Science (Dr. David Hill), Eurotrial 40 (Dr. Marco Rosselli del Turco), History and Development of Intravenous Feeding and Use in Cancer Therapy (Dr. Jonathan Rhoads), Cytopathology (Dr. William Frable), Laparoscopic Surgery (Dr. Bruce Ramshaw), Radiology for the Year 2000 (Dr. Carl d'Orsi), Breast Cancer (Dr. Kirby Bland), Rectal Cancer (Dr. Glen Steele), Prostate Cancer (Dr. Michael Brawer), Cervical Cancer (Dr. Hervy Averette), Lymphoma (Dr. Charles Coltman), Chronic Leukemias (Dr. Heinz Ludwig), and Soft Tissue Sarcoma (Dr. Murray Brennan).
A recent report that 93 per cent of invasive cervical cancers worldwide contain human papillomavirus (HPV) may be an underestimate, due to sample inadequacy or integration events affecting the HPV L1 gene, which is the target of the polymerase chain reaction (PCR)-based test which was used. The formerly HPV-negative cases from this study have therefore been reanalyzed for HPV serum antibodies and HPV DNA. Serology for HPV 16 VLPs, E6, and E7 antibodies was performed on 49 of the 66 cases which were HPV-negative and a sample of 48 of the 866 cases which were HPV-positive in the original study. Moreover, 55 of the 66 formerly HPV-negative biopsies were also reanalyzed by a sandwich procedure in which the outer sections in a series of sections are used for histological review, while the inner sections are assayed by three different HPV PCR assays targeting different open reading frames (ORFs). No significant difference was found in serology for HPV 16 proteins between the cases that were originally HPV PCR-negative and -positive. Type-specific E7 PCR for 14 high-risk HPV types detected HPV DNA in 38 (69 per cent) of the 55 originally HPV-negative and amplifiable specimens. The HPV types detected were 16, 18, 31, 33, 39, 45, 52, and 58. Two (4 per cent) additional cases were only HPV DNA-positive by E1 and/or L1 consensus PCR. Histological analysis of the 55 specimens revealed that 21 were qualitatively inadequate. Only two of the 34 adequate samples were HPV-negative on all PCR tests, as against 13 of the 21 that were inadequate ( p< 0.001). Combining the data from this and the previous study and excluding inadequate specimens, the worldwide HPV prevalence in cervical carcinomas is 99.7 per cent. The presence of HPV in virtually all cervical cancers implies the highest worldwide attributable fraction so far reported for a specific cause of any major human cancer. The extreme rarity of HPV-negative cancers reinforces the rationale for HPV testing in addition to, or even instead of, cervical cytology in routine cervical screening.
The antibody response to papillomaviruses is a key determinant of protective immunity. HPV serology is also an important epidemiological tool for the assay of past and present HPV infections and for prediction of HPV-associated cancers and their precursor lesions. This review focuses on the assay of antibody responses to the HPV capsid, its use as a marker of cumulative HPV exposure and surveys how HPV seroepidemiology has been used to elucidate the spread of HPV infection in various populations, the natural history of HPV infection and that exposure to HPV is associated with increased risk for several human cancers.
Human papillomaviruses (HPVs) play an essential role in the etiology of cervical cancer, but besides an established role for sexual transmission, little is known about other risk factors for HPV infection. Risk factors for nononcogenic, oncogenic, and HPV 16 cervical infections were investigated using a cumulative case-control approach nested in an ongoing cohort study of low income women from São Paulo, Brazil. HPV DNA was detected and typed by the MY09/11 PCR protocol. Risk factor information was obtained via interviews. In a case-control analysis, we compared women who harbored infections with exclusively nononcogenic types (n = 123), exclusively oncogenic types (n = 94), and any HPV 16 (n = 60) to women remaining HPV-negative (n = 512) throughout 1 year of follow-up. A strong negative association was found between age and oncogenic infections, but not with nononcogenic infections. Oral contraceptive use was strongly and exclusively associated with oncogenic and HPV 16 infections. Markers of sexual activity were associated with all types of infections, although with varying strengths. Our results suggest some important differences in the epidemiological correlates of HPV infection according to oncogenicity that may have implications for the-planning of specific preventive strategies aiming at reduction of cervical cancer risk.
To evaluate the accuracy of conventional and new methods of Papanicolaou (Pap) testing when used to detect cervical cancer and its precursors.
Systematic search of English-language literature through October 1999 using MEDLINE, EMBASE, other computerized databases, and hand searching.
All studies that compared Pap testing (conventional methods, computer screening or rescreening, or monolayer cytology) with a concurrent reference standard (histologic examination, colposcopy, or cytology).
Two reviewers independently reviewed selection criteria and completed 2 x 2 tables for each study.
94 studies of the conventional Pap test and three studies of monolayer cytology met inclusion criteria. No studies of computerized screening were included. Data were organized by cytologic and histologic thresholds used to define disease. For conventional Pap tests, estimates of sensitivity and specificity varied greatly in individual studies. Methodologic quality and frequency of histologic abnormalities also varied greatly between studies. In the 12 studies with the least biased estimates, sensitivity ranged from 30% to 87% and specificity ranged from 86% to 100%.
Insufficient high-quality data exist to estimate test operating characteristics of new cytologic methods for cervical screening. Future studies of these technologies should apply adequate reference standards. Most studies of the conventional Pap test are severely biased: The best estimates suggest that it is only moderately accurate and does not achieve concurrently high sensitivity and specificity. Cost-effectiveness models of cervical cancer screening should use more conservative estimates of Pap test sensitivity.
Viruses that belong to six different families are a significant cause for neoplasia in man and animals. Among them are the Papillomaviruses that cause uterine cervical cancer in women. Efforts to develop prophylactic vaccines against viruses that cause cancer are now a major research engagement. Vaccinology, the science of vaccines, engages the sciences of immunology and of microbiology, both relying heavily on molecular biology. Successful development of vaccines relies on extensive knowledge of immunology and vaccinology. Present efforts to develop vaccines against cervical cancer caused by Papillomaviruses are focused on use of the structural antigens L1 and L2 of the virus and on the oncoproteins E6 and E7. Work on Papillomavirus vaccines has been brilliantly conceived and executed and some of vaccines are now in clinical trial. Success may follow and Papillomavirus vaccine may join with the hepatitis B virus anti-cancer vaccine in the battle against cancers of man.