The biology and significance of human papillomavirus infections in the genital tract.

A variety of human papillomavirus (HPV) types infect the anogenital mucosa, giving rise to lesions that differ in clinical appearance, histology, and risk of malignant progression. Certain high-risk types (HPVs 16, 18, 31, 33, 35 and 39) have a strong association with high-grade epithelial neoplasia and invasive carcinomas of the anogenital tract. Cancer appears to have a multifactorial etiology, and HPV infection alone is probably insufficient for malignant transformation. The consistent association between HPV infection and anogenital cancers emphasizes, however, that the sexually transmitted papillomaviruses may have a necessary role in carcinogenesis. Hence, there is a prospect that vaccination programs may one day allow public health control of HPV infection, thereby eliminating an important risk factor.     

Serologically diagnosed infection with human papillomavirus type 16 and risk for subsequent development of cervical carcinoma: nested case-control study.

OBJECTIVE--To study human papillomavirus type 16 in the aetiology of cervical carcinoma. DESIGN--Within a cohort of 18814 Finnish women followed up to 23 years a nested case-control study was conducted based on serological diagnosis of past infection with human papillomavirus type 16. SUBJECTS--72 women (27 with invasive carcinoma and 45 with in situ carcinoma) and 143 matched controls were identified during the follow up. MAIN OUTCOME MEASURE--Relative risk of cervical carcinoma in presence of IgG antibodies to human papillomavirus type 16. RESULTS--After adjustment for smoking and for antibodies to various other agents of sexually transmitted disease, such as herpes simplex virus type 2 and Chlamydia trachomatis, the only significant association was with infection with human papillomavirus type 16 (odds ratio 12.5; 95% confidence interval 2.7 to 57, 2P<0.001). CONCLUSION--This prospective study provides epidemiological evidence that infection with human papillomavirus type 16 confers an excess risk for subsequent development of cervical carcinoma.     

外阴皮肤营养不良组织中人乳头瘤病毒DNA的检测

采用Southern Blot分子杂交方法检测了9例外阴皮肤营养不良组织中人乳头瘤病毒DNA的存在情况。结果显示8例增生型营养不良组织中,2例HPV-16阳性,1例HPV33阳性,在3例组织中探测到HPV16相关序列,在1例混合型中也检测到HPV16相关序例,HPV DNA的总检出率为77％。结果提示外阴皮肤营养不良的发生可能与HPV感染有关。     

Properties of p53 mutations detected in primary and secondary cervical cancers suggest mechanisms of metastasis and involvement of environmental carcinogens.

Primary human papillomavirus (HPV) positive anogenital cancers normally develop without somatic mutation within the p53 gene. In this study, however, we have identified p53 point mutations in metastases arising from HPV positive cervical carcinomas, suggesting that acquisition of p53 mutation may play a role in the progression of some HPV associated primary cancers. p53 mutants identified in anogenital cancers exhibit a dominant transforming phenotype and increased resistance to HPV16 E6 directed degradation. The association of p53 mutation with metastases may explain the poor prognosis reported for HPV negative primary cancers, many of which already contain mutant p53. A high proportion of p53 mutations detected in both primary and metastatic cancers are GC-->TA transversions, strongly suggesting a role for external carcinogens in the development of these cancers.     

Papillomaviruses—to vaccination and beyond

High risk human papillomavirus (HPV) types 16 and 18 DNAs were initially identified in 1983-1984. Subsequently the DNA of several other high risk HPV types has been identified. HPV 16 is present in more than 50% of cervical cancer biopsies, and HPV 18 is close to 20%. Some geographic variations exist in the prevalence of HPV high risk types: e.g. HPV 45 is more frequently observed in equatorial Africa, whereas types 58 and 52 have been more often found in East Asia. Molecular as well as epidemiological studies demonstrate that high risk HPV are indeed the causative agents for cervical cancer, they are also involved in other anogenital cancers, and in 25-30% of oropharyngeal carcinomas. Some of the mechanistic aspects are discussed in this review.     

Papilloma formation in human foreskin xenografts after inoculation of human papillomavirus type 16 DNA.

A mouse model of high-risk human papillomavirus infection was developed in which human papillomavirus (HPV) type 16 DNA was inoculated into human foreskin grafted to the skin of severe combined immunodeficient (scid) mice. Grafted skin contained human epidermis and dermis and, like normal human skin, expressed involucrin in differentiating keratinocytes. HPV type 16 DNA, attached to gold particles, was delivered directly into human epidermal cells and induced exophytic papilloma with histologic features of papillomavirus infection, including koilocytosis and expression of papillomavirus capsid antigen. This model should be useful for determining in vivo the functions of viral genes and for developing strategies to prevent and treat HPV-associated disease. It may also be of value in developing animal models of other human skin diseases.     

The human papillomavirus type 16 E7 oncoprotein activates the Fanconi anemia (FA) pathway and causes accelerated chromosomal instability in FA cells

Fanconi anemia (FA) patients have an increased risk for squamous cell carcinomas (SCCs) at sites of predilection for infection with high-risk human papillomavirus (HPV) types, including the oral cavity and the anogenital tract. We show here that activation of the FA pathway is a frequent event in cervical SCCs. We found that FA pathway activation is triggered mainly by the HPV type 16 (HPV-16) E7 oncoprotein and is associated with an enhanced formation of large FANCD2 foci and recruitment of FANCD2 as well as FANCD1/BRCA2 to chromatin. Episomal expression of HPV-16 oncoproteins was sufficient to activate the FA pathway. Importantly, the expression of HPV-16 E7 in FA-deficient cells led to accelerated chromosomal instability. Taken together, our findings establish the FA pathway as an early host cell response to high-risk HPV infection and may help to explain the greatly enhanced susceptibility of FA patients to squamous cell carcinogenesis at anatomic sites that are frequently infected by high-risk HPVs.     

Association between HLA DQB1 * 03 and cervical intra-epithelial neoplasia.

BACKGROUND: Cervical intraepithelial neoplasia (CIN) and cervical cancer have been shown to be strongly associated with infection by human papillomavirus (HPV). However, other factors may be contributory in the progression from normal epithelium to CIN and cervical cancer, since not all women with HPV infection develop disease. Recently, it was demonstrated that there is a high risk for cervical cancer and CIN in women with HLA DQB1 * 03 (RR = 7.1, p < 0.0009) (1). Subsequent reports have been conflicting, due to sample size, genetic heterogeneity and differences in the techniques employed for the detection of HLA DQB1 * 03. MATERIALS AND METHODS: DNA from cervical smears of 178 women with CIN and 420 controls with normal cervical cytology was analyzed by polymerase chain reaction (PCR) with type-specific primers for HPV 16, 18, 31, and 33. The DNA from test and control samples were also analyzed by a novel PCR technique, which mutates the first base of codon 40 (DQ alleles) from T to G to create an artificial restriction site for an enzyme Mlu I that distinguish DQB1 * 03 from other alleles and are confirmed by digestion of amplified DNA with Mlu I. Further analysis of individual DQB1 * 03 alleles was performed using PCR and allele-specific primers. RESULTS: One hundred forty-four (34%) out of 420 controls (all HPV 16, 18, 31, or 33 negative and normal cytology), 37/66 (56%) of CIN I and 72/112 (64%) of CIN III were positive for DQB1 * 03 (trend test, p < 0.001, chi 2 = 37.3). A significant association was observed between DQB1 * 03 and CIN (odds ratio 3.03; 95% CI 2.11-3.45). Of women with CIN, 131/178 (73.5%) had HPV (types 16, 18, 31, or 33) infection. There was a significant association between DQB1 * 03 and presence of HPV (odds ratio 3.43; 95% CI 2.25-5.10). Homozygosity for DQB1 * 03 was more strongly associated with CIN than heterozygosity (odds ratios 4.0 and 2.63, respectively); and for the presence of HPV (odds ratio 4.47; 95% CI 2.58-7.77). HLA DQB1 * 0301 was the most strongly associated allele with CIN and HPV (odds ratios 2.53 and 2.63, respectively). CONCLUSIONS: HLA DQB1 * 03 is associated significantly with CIN and may be permissive for HPV infection. Further analysis of class II HLA typing in CIN is necessary to evaluate this association.     

Risk factors for infection with human immmunodeficiency virus among European expatriates in Africa.

The pattern of cases of AIDS in Belgium suggests that Europeans infected with human immunodeficiency virus (HIV) acquired the infection in Africa. The prevalence of infection was assessed in Belgian advisers and European expatriates and risk factors for infection defined in a case-control study of expatriate men. Fifteen (1.1%) of 1401 Belgian advisers working in Africa and 41 (0.9%) of 4564 European expatriates living in Africa, were positive for antibody to HIV in a voluntary screening programme in Belgium. Among subjects with antibody to HIV the ratio of men to women was 3:1. These subjects did not have a history of intravenous drug abuse or blood transfusion and only one was homosexual. In a case-control study of 33 expatriate men who had antibody to HIV and 119 controls the men with antibody reported significantly more female sexual partners, who were more commonly local; and significantly more sexual contact with prostitutes in Africa. They had a significantly higher prevalence of history of sexually transmitted disease and had received significantly more injections by unqualified staff in Africa during the previous five years. No specific sexual practices were associated with having antibody to HIV. After multivariate analysis sexual contact with local women (adjusted odds ratio 14.7; 95% confidence interval 2.81 to 76.9), sexual contact with prostitutes (adjusted odds ratio 10.8 (1.6 to 71.9), and injections by unqualified staff (adjusted odds ratio 13.5 (3.7 to 49.8) remained independent risk factors for infection. European expatriates in Africa were at increased risk from infection with HIV and were a means of introducing HIV into the heterosexual population in Europe. Transmission from women to men by vaginal intercourse seemed to be the most probable route of infection.     

门诊阴道镜检查患者阴道菌群构成与HPV16感染的关系

目的 探讨门诊阴道镜检查患者阴道菌群构成与HPV16感染的关系.方法 选取我院2016年3月-2018年12月门诊阴道镜检查的高危HPV感染患者96例为研究对象,通过阴道镜检查结果分析其HPV16感染情况、阴道菌群构成及菌群多样性.结果 HPV16阳性组人数41例,阴性组55例,感染率为42.7％.HPV16阳性组患者...     

Focus: A Multifaceted Battle Against Cancer: Nuns,Warts, Viruses,and Cancer

It has been known for more than 150 years that the risk of carcinoma of the uterine cervix correlates with the number of sexual partners. Laboratory and epidemiological evidence demonstrated that infection with certain human papillomavirus (HPV) types initiates the vast majority of, if not all, cervical cancer, as well as a substantial fraction of other cancers, including other anogenital cancer and oropharyngeal cancer. Pap smear testing resulted in a dramatic reduction in the incidence of cervical cancer in the developed world, and HPV vaccination has the potential to eradicate HPV-associated cancer worldwide and represents a major public health breakthrough. The major current challenge is to ensure that HPV vaccines are widely administered.     

HPV16 Seropositivity and Subsequent HPV16 Infection Risk in a Naturally Infected Population: Comparison of Serological Assays

Background

Several serological assays have been developed to detect antibodies elicited against infections with oncogenic human papillomavirus (HPV) type 16. The association between antibody levels measured by various assays and subsequent HPV infection risk may differ. We compared HPV16-specific antibody levels previously measured by a virus-like particle (VLP)-based direct enzyme-linked immunoassay (ELISA) with levels measured by additional assays and evaluated the protection against HPV16 infection conferred at different levels of the assays.

Methodology/Principal Findings

Replicate enrollment serum aliquots from 388 unvaccinated women in the control arm of the Costa Rica HPV vaccine trial were measured for HPV16 seropositivity using three serological assays: a VLP-based direct ELISA; a VLP-based competitive Luminex immunoassay (cLIA); and a secreted alkaline phosphatase protein neutralization assay (SEAP-NA). We assessed the association of assay seropositivity and risk of subsequent HPV16 infection over four years of follow-up by calculating sampling-adjusted odds ratios (OR) and HPV16 seropositivity based on standard cutoff from the cLIA was significantly associated with protection from subsequent HPV16 infection (OR = 0.48, CI = 0.27–0.86, compared with seronegatives). Compared with seronegatives, the highest seropositive tertile antibody levels from the direct ELISA (OR = 0.53, CI = 0.28–0.90) as well as the SEAP-NA (OR = 0.20, CI = 0.06, 0.64) were also significantly associated with protection from HPV16 infection.

Conclusions/Significance

Enrollment HPV16 seropositivity by any of the three serological assays evaluated was associated with protection from subsequent infection, although cutoffs for immune protection were different. We defined the assays and seropositivity levels after natural infection that better measure and translate to protective immunity.     

Human papillomavirus infection and neoplasia of the cervix and anogenital region in women with Hodgkin's disease

Immunosuppression has been associated with an increased incidence of condyloma and neoplasia of the cervix and anogenital region, lesions associated with human papillomavirus (HPV) infection. The role of immunosuppression as a risk factor for the development of these lesions in patients with Hodgkin's disease was studied in a series of 666 consecutive women seen at the University of Texas M. D. Anderson Hospital between 1963 and 1982. Thirty-nine patients (5.9%) of the entire series and 45.9% of the 85 women with Hodgkin's disease who had a gynecologic examination showed evidence of condyloma, dysplasia or carcinoma of the cervix or anogenital region. This is a significantly greater percentage of affected women than would be expected based on published results from Papanicolaou screening services. The evidence is compatible with immunosuppression from Hodgkin's disease or its treatment rendering a woman susceptible to persistent HPV infection and its consequences.     

The interaction of high and low-risk human papillomavirus genotypes increases the risk of developing genital warts: A population-based cohort study

Cervical cancer is among the most common type of cancers in women and is associated with human papillomavirus (HPV) infection. Genital warts are also reported to be linked with HPV infection types 11 and 6. In turn, clinical characteristics and morphological features of warts may be useful in the prediction of prognosis and in making treatment decisions. Thus, we have investigated the association of high and low-risk HPVs genotype with genital wart risk, as well as pathological and cytological information in cases recruited from a population-based cohort study of 1380 patients. Patients infected with HPV genotype 6 or 11 had an increased risk of having warts, with OR of 2.34 (95% CI: 0.955-5.737, P = 0.06). Also, this association was enhanced in the presence of high plus low-risk HPV for having genital wart (OR: 2.814; 95%: 1.208-6.55, P = 0.017) and cases having high-risk HPV (OR: 2.329; 95% CI: 1.029-5.269, P = 0.042). Moreover, we observed patients with genital warts having CIN2/3, indicating the importance of informing the physician to the patient to prevent more severe lesions. Our data demonstrated that patients with both low/high-risk HPV types had an increased risk of developing genital warts and persistent infection with HPV was a necessary precursor for the increase in cervical lesions.     

High risk human papillomavirus and Epstein Barr virus in human breast milk

ABSTRACT: BACKGROUND: Multiple viruses, including human immunodeficiency virus, Epstein Barr virus (EBV) and mouse mammary tumour virus have been identified in human milk. High risk human papillomavirus (HPV) sequences have been identified in breast cancer. The aim of this study is to determine if viral sequences are present in human milk from normal lactating women. FINDINGS: Standard (liquid) and in situ polymerase chain reaction (PCR) techniques were used to identify HPV and EBV in human milk samples from normal lactating Australian women who had no history of breast cancer.High risk human papillomavirus was identified in milk samples of 6 of 40 (15%) from normal lactating women - sequencing on four samples showed three were HPV 16 and one was HPV 18. Epstein Barr virus was identified in fourteen samples (33%). CONCLUSION: The presence of high risk HPV and EBV in human milk suggests the possibility of milk transmission of these viruses. However, given the rarity of viral associated malignancies in young people, it is possible but unlikely, that such transmission is associated with breast or other cancers.     

Human Papillomavirus: Confronting the Epidemic-A Urologist's Perspective

The human papillomavirus (HPV) has long been associated with the development of penile lesions-condyloma acuminatum and verrucous carcinoma of the penis. More recently, HPV has been implicated as an etiology of more serious neoplasias in men-penile carcinoma and other anogenital squamous-cell carcinomas. HPV is now widely recognized as responsible for more than 95% of cervical cancers in women. HPV seems to have been receiving relatively scant attention to date-from physicians in general, and particularly from urologists-as a venereal disease of significant concern. Yet HPV is recognized to be the most frequently acquired sexually transmitted viral infection worldwide. It is estimated that approximately 6 million new cases of HPV are sexually transmitted annually in the United States. Fortunately, many, if not most, of these HPV infections are transient. However, each newly acquired infection has the potential to persist as an incurable, lifelong affliction, generating a significant increase in the long-term risk of cancer for patients and their sexual partners. Many of these HPV-related cancers will not become manifest until decades later.     

Genital transmission of HPV in a mouse model is potentiated by nonoxynol-9 and inhibited by carrageenan

Genital human papillomavirus (HPV) infection is the most common sexually transmitted infection, and virtually all cases of cervical cancer are attributable to infection by a subset of HPVs (reviewed in ref. 1). Despite the high incidence of HPV infection and the recent development of a prophylactic vaccine that confers protection against some HPV types, many features of HPV infection are poorly understood. It remains worthwhile to consider other interventions against genital HPVs, particularly those that target infections not prevented by the current vaccine. However, productive papillomavirus infection is species- and tissue-restricted, and traditional models use animal papillomaviruses that infect the skin or oral mucosa. Here we report the development of a mouse model of cervicovaginal infection with HPV16 that recapitulates the establishment phase of papillomavirus infection. Transduction of a reporter gene by an HPV16 pseudovirus was characterized by histology and quantified by whole-organ, multispectral imaging. Disruption of the integrity of the stratified or columnar genital epithelium was required for infection, which occurred after deposition of the virus on the basement membrane underlying basal keratinocytes. A widely used vaginal spermicide, nonoxynol-9 (N-9), greatly increased susceptibility to infection. In contrast, carrageenan, a polysaccharide present in some vaginal lubricants, prevented infection even in the presence of N-9, suggesting that carrageenan might serve as an effective topical HPV microbicide.     

Human Papillomavirus-Associated Subsequent Malignancies among Long-Term Survivors of Pediatric and Young Adult Cancers

Long-term survivors of pediatric and young adult (PAYA) cancers have a high incidence of subsequent neoplasms, but few risk factors other than cancer treatment have been identified. We aimed to describe the burden of human papillomavirus (HPV)-associated malignancies among survivors of PAYA cancers to assess whether HPV infections might be a reasonable area of future etiologic research on subsequent malignancies in this population. We used longitudinal data from 9 population-based registries of the Surveillance, Epidemiology, and End Results program collected between 1973 and 2010 to assemble a cohort of individuals who were diagnosed with any cancer between the ages of 0 and 29 years and survived at least 5 years post-diagnosis. We estimated sex-specific standardized incidence ratios (SIRs) with corresponding 95% confidence limits (CL) of HPV-associated subsequent malignancies (cervical, vaginal, vulvar, penile, anal, tongue, tonsillar, and oropharyngeal). Our study population comprised 64,547 long-term survivors of PAYA cancers diagnosed between 1973 and 2010. Compared with females in the general US population, female PAYA cancer survivors had a 40% relative excess of HPV-associated malignancies overall (SIR = 1.4, 95% CL: 1.2, 1.8). Compared with males in the general US population, male PAYA cancer survivors had a 150% relative excess of HPV-associated malignancies overall (SIR = 2.5, 95% CL: 1.9, 3.4). Our findings suggest an excess of HPV-associated malignancies among PAYA cancer survivors compared with the general US population. We hypothesize that a portion of subsequent malignancies among PAYA cancer survivors may be directly attributable to HPV infection. This hypothesis warrants exploration in future studies.     

Comparison between the polymerase chain reaction and slot blot hybridization for the detection of HPV sequences in cervical scrapes

Sixty-four women presenting with a single mildly abnormal smear were investigated for infection with human papillomavirus (HPV) type 16 using both slot blot hybridization and polymerase chain reaction (PCR) amplification. PCR was nearly three times more sensitive for the detection of HPV 16 DNA than slot blot hybridization. HPV 16 was not significantly associated with a risk of progression to CIN if PCR was used to screen for infection. Women who smoked were at significantly greater risk of progression to CIN than non-smokers.