HPV Virus Medical - General Information

McPartland TS, Weaver BA, Lee SK, Koutsky LA. Yale University School of Medicine, Department of Pediatrics, New Haven, Connecticut 06520, USA. tara.mcpartland@yale.edu

The authors assessed young men's knowledge and perceptions of genital human papillomavirus (HPV) infection to identify factors that predict intention to make positive behavioral changes. Male university students aged 18 to 25 years completed a self-report instrument to assess knowledge and perceptions of genital HPV infection. If diagnosed with HPV, most men (95%) reported that they would use condoms with new partners. The intention to reduce number of sex partners was associated with an understanding that HPV may have severe consequences for women, whereas intention to encourage female sex partners to undergo Pap smear screening was associated with increased general knowledge of HPV infection. The authors concluded that it is important to include men in HPV education and prevention efforts, especially within the context that HPV may lead to cervical cancer in female partners.

Obstet Gynecol. 2005 Apr;105(4):905-18.

ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists. Number 61, April 2005. Human papillomavirus.

American College of Obstetricians and Gynecologists.

More than 15 years ago, a relationship between human papillomavirus (HPV) infection and cervical cancer was recognized. Since then, important strides in understanding the virus have been made, particularly in the following areas: modes of transmission and risk factors associated with transmission; the oncogenic potential of specific viral types and the mechanism by which they cause cancer; and the spectrum of infection, ranging from asymptomatic carrier states to overt warts, preneoplastic lesions, and invasive cancer. Sophisticated new tests for the detection of HPV that hold great promise for improved screening for cervical cancer precursors and invasive cancer and for the triage of abnormal cervical cytology also have been developed. Understanding the immunology of HPV has allowed the development of new and more effective treatment modalities for HPV infection and the preliminary development of primary prevention modalities, including HPV vaccines.

Publication Types:
• Guideline
• Practice Guideline

Med Wieku Rozwoj. 2004;VIII(3 Pt 2):733-743.

Human Papilloma Virus infection - the major infectious factor in the process of cervical intraepithelial neoplasia.

HPV Virus Medical - Article in Polish

In spite of increasing knowledge concerning cervical cancer; and the documented role of Human Papilloma Virus (HPV) - as a major causing factor; there have been no changes in the epidemiological situation of this disease, especially in our country. Cytological screening has made crucial impact on decreasing mortality in that carcinoma. HPV involvement in cervical neoplasia and new diagnostic methods give possibility for early diagnosis of cervical lesions and to identify the group of women with higher risk of cervical cancer Nevertheless there are no strict recommendations concerning HPV diagnostic procedures especially in the mass screening programmes. Therapeutic methods, specifically for HPV infection are still unknown. Based on the above, questions arise, if it is medically and financially justifiable to detect HPV infection? What is the clinical algorithm for the management of infected patient? And what is the future treatment?

Immunology. 2005 May;115(1):136-49.

Induction of human papillomavirus type 16-specific immunologic responses in a normal and an human papillomavirus-infected populations.

Cheng WF, Lee CN, Su YN, Chang MC, Hsiao WC, Chen CA, Hsieh CY. Department of Obstetrics and Gynecology, National Taiwan University, Taipei, Taiwan.

Human papillomavirus (HPV) infection, especially with the oncogenic genotypes, is the most important risk factor for developing cervical cancer. We focused on generating HPV16 E7-specific cytotoxic CD8(+) T lymphocytes and evaluating HPV16 E7-specific immune responses in HPV16-infected and uninfected populations. Peripheral blood mononuclear cells (PBMCs) were first collected from an uninfected group with an human lymphocyte antigen (HLA) A2 haplotype (four volunteers). Mature monocyte-derived dendritic cells (DCs) were generated from the PBMCs and pulsed with one of two HLA-A2-restricted E7 peptides, aa 11-20 [YMLDLQPETT] and aa 86-93 [TLGIVCPI], as antigen presenting cells. The autologous naive or cultured PBMCs were then cultured with peptide-pulsed DCs to detect the HPV16 E7-specific immune responses by a variety of techniques such as enzyme-linked immunosorbent assay (ELISA), enzyme-linked immunospot (ELISPOT) assay and cytotoxic T lymphocyte assay. Interferon-gamma (IFN-gamma) from E7-specific cytotoxic CD8(+) T lymphocytes stimulated with the respective peptide was detected by ELISA. Using ELISPOT analysis, a marked increase in the number of IFN-gamma-secreting CD8(+) E7-specific lymphocytes was observed following peptide stimulation. Cultured CD8(+) T lymphocytes were highly cytotoxic against the CaSki cells. PBMCs were then collected from an HPV16-infected population of the HLA-A2 haplotype, including four persons of HPV16 infection only, four with cervical intraepithelial neoplasia (CIN) lesions, and four cervical cancer patients. We then compared the immunologic responses to E7 between HPV16-infected and uninfected populations by ELISA and ELISPOT assay. The E7-specific immunologic responses of the HPV16-infected populations were significantly higher than those of the uninfected population. In addition, persons with an HPV16 infection only or those with CIN lesions generated higher E7-specific immunologic responses than cervical cancer patients. Our results demonstrate methods for evaluating E7-specific immunologic responses and reflect the biological responses of HPV16-infected people during different periods of cervical disease.

Acta Cytol. 2005 Mar-Apr;49(2):127-31.
Comment in:

Genital human papillomavirus testing by in situ hybridization in liquid atypical cytologic materials and follow-up biopsies.

Bewtra C, Xie Q, Soundararajan S, Gatalica Z, Hatcher L. Department of Pathology, Creighton University Medical Center, Omaha, Nebraska 68131, USA.

OBJECTIVE: To describe cases of HPV testing by DNA in situ hybridization performed on atypical cervicovaginal samples collected by a liquidsed method that were negative for HPV DNA on cytology but revealed cervical intraepithelial neoplasia on follow-up biopsies. STUDY DESIGN: Three hundred ninety-five consecutive SurePath atypical squamous cells of undetermined significance (ASC-US) cytologic samples from asymptomatic, reproductive-age women were tested for human papillomaviruses (HPVs) by the in situ hybridization (ISH) method (Ventana Inform HPV Test, Tucson, Arizona, U.S.A). One hundred (25%) cases underwent follow-up colposcopic biopsy within 3 months of cytology. All the tests (cytology, ISH, histology) were independently evaluated without knowledge of the other tests. RESULTS: One hundred twenty-two (33%) cytologic samples were positive for HPVs. Of a total of 100 (HPV positive and negative) follow-up biopsies, 55 were positive for cervical intraepithelial neoplasia (CIN). Fourteen cases of biopsy-proven CIN tested negative for all HPV types in the prior cytologic samples. Retesting of the 14 CIN tissues by ISH was negative in 10, positive for HPV in 2 and inconclusive in 2. CONCLUSION: There is a small but significant (14%) false negative rate with HPV testing by the Ventana ISH method. Clinically suspicious cases should be followed even if an HPV test is negative.

Clin Cancer Res. 2005 Apr 15;11(8):2862-7.

Colorectal papillomavirus infection in patients with colorectal cancer.

Bodaghi S, Yamanegi K, Xiao SY, Da Costa M, Palefsky JM, Zheng ZM. HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.

PURPOSE: Infection with human papillomaviruses (HPV) is associated with the development of cervical cancer, but whether HPVs have a role in colorectal cancer remains controversial.Experimental Designs: To determine the relationship between HPV and colorectal cancer, we did a retrospective, controlled study using tumor and tumor-adjacent colorectal tissues dissected from patients with colorectal cancer, as well as colorectal tissues from control individuals with no cancer. The samples were processed in a blinded fashion for nested PCR and in situ PCR detection of HPV DNAs. The PCR products were gel-purified and sequenced for HPV genotyping.RESULTS: We found that colorectal tissues from 28 of 55 (51%) patients with colorectal cancer were positive for HPV DNA. Colorectal tissues from all 10 control individuals were negative for HPV DNA (P = 0.0034). Of the 107 usable (GAPDH(+)) samples collected as paired colorectal tissues (tumor and tumor-adjacent tissues) from the patients, 38 (36%) had HPV16 (n = 31), HPV18 (n = 5), or HPV45 (n = 2), with HPV DNA in both tumor and tumor-adjacent tissues of 10 paired samples, 13 in only the tumor, and 5 in only tumor-adjacent tissues. In situ PCR detection of the tumor tissues confirmed the presence of HPV DNA in tumor cells.CONCLUSION: Our results suggest that colorectal HPV infection is common in patients with colorectal cancer, albeit at a low DNA copy number, with HPV16 being the most prevalent type. HPV infection may play a role in colorectal carcinogenesis.

Proteomics. 2005 Apr;5(6):1481-93.

Proteomic analysis of progressive factors in uterine cervical cancer.

Choi YP, Kang S, Hong S, Xie X, Cho NH. Brain Korea 21 Project for Medical Science, Yonsei University, Seoul, South Korea.

Human papillomavirus (HPV) infections play a crucial role in the progress of cervical cancer. The high-risk HPV types are frequently associated with the development of malignant lesions. Some of the latest studies have demonstrated that the high-risk HPV 16 and 18 are predominantly detected in the more aggressive cancers. In the present study, we aimed to establish the proteomic profiles and characterization of the tumor related proteins by using two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS). For proteomic analysis, patients infected by HPV 16 or 18 were included in this study. We compared nuclear protein and cytoplasmic protein, separately by using the subcellular fraction. Differential protein spots between cervical cancer with high-risk HPV, HPV 16 or HPV 18, and HaCaT cell lines were characterized by 2-DE. Those proteins analyzed by peptide mass fingerprinting based on MALDI-TOF MS and database searching were the products of oncogenes or proto-oncogenes, and the others were involved in the regulation of cell cycle, for general genomic stability, telomerase activation, and cell immortalization. However, there was no difference in protein characterization for cervical cancer between HPV 16 and HPV 18 infection. Nonetheless, these data are valuable for the mass identification of differentially expressed proteins involved in human uterine cervical cancer. Moreover, the data has enormous value for establishing the human uterine cervical cancer proteome database that can be used in screening a molecular marker for the further study of human uterine cervical cancer, and also for studying any correlation among the cancers induced by HPV.

Georgian Med News. 2005 Mar;(3):30-3.

The state of cervical and vaginal epithelial tissue in patients with hpv infection.

HPV Virus Medical - Article in Russian

Genital human papilloma virus (HPV) infection is the sexually transmitted disease. HPV induces the proliferation of epithelial cells. In the areas of viral inclusions vulvovaginal warts, papillomas and condylomas are developing. Some serotypes of HPV are known as a significant risk factor of cervical cancer. The aim of our study was to detect the conditions of oxidation processes in vaginal and cervical tissues in patients with HPV infection. According to our results, in patients with HPV, intensification of production of reactive forms of nitrogen and oxygen in vaginal and cervical tissues takes place which is the result of activation of leukocytes, other phagocyte cells and chaotic flow of blood in damaged tissue, as well as interchanging periods of hypoxia and reperfusion.

Gynecol Oncol. 2005 May 12; [Epub ahead of print]

Immunosuppressive activity of proteases in cervical carcinoma.

Daneri-Navarro A, Del Toro-Arreola S, Sanchez-Hernandez PE, Ramirez-Duenas MG, Armendariz-Borunda J, Perez-Montfort R. Programa de Doctorado en Ciencias Biomedicas, Departamento de Fisiologia, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, 44340 Guadalajara, Jalisco, Mexico. de la Salud, Universidad de Guadalajara, Jalisco, Mexico.

OBJECTIVE.: The host immune response is essential for restraining both HPV infections and HPV-related cervical cancer. We previously reported a direct correlation between proteolytic activity and malignant progression from precursor lesions to invasive cervical carcinoma. The present study was undertaken to investigate whether proteinases from cervical carcinoma extracts and representative purified proteinases involved in tumor progression could regulate lymphocyte proliferation to phytohemagglutinin (PHA) mitogen. METHODS.: Extracts were prepared from tissue samples obtained from patients with invasive cervical squamous carcinoma, squamous intra-epithelial lesions or women with normal cervix. Lymphocytes obtained from a single healthy donor were pre-incubated with one of these extracts in the presence or absence of proteinase inhibitors, and stimulated with PHA during 72 h. The proliferative response was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) method (re-validated with thymidine uptake). RESULTS.: Lymphocyte proliferation was significantly decreased by cervical carcinoma extracts, while only slightly decreased by squamous intra-epithelial lesions or normal extracts. Inhibitor assays indicated that proteinases from cervical carcinoma were responsible for 53.30% of total suppressive activity. We found that purified enzymes such as trypsin, cathepsin B, uPA and type IV collagenase suppressed the proliferative response in a dose-dependent fashion. CONCLUSIONS.: Our data suggest that in addition to the classic role in tumor invasion, proteases could represent an immune evasion mechanism in cervical carcinoma.

Cancer Genet Cytogenet. 2005 May;159(1):44-47.

Association between the stages of cervical cancer and chromosome 1 aneusomy.

Cortes-Gutierrez EI, Davila-Rodriguez MI, Muraira-Rodriguez M, Said-Fernandez S, Cerda-Flores RM. Genetics Division, Centro de Investigacion Biomedica del Noreste (CIBIN), Instituto Mexicano del Seguro Social (IMSS), Administracion de Correos No. 4, Apartado postal 20, C.P. 64720 Monterrey, Nuevo Leon, Mexico; Facultad de Ciencias Biologicas (FCB), Universidad Autonoma de Nuevo Leon (UANL), Monterrey, Nuevo Leon, Mexico.

The high-risk human papillomavirus is known to play a pivotal role in cervical carcinogenesis. Numerical and structural aberrations are known to be related to different behaviors of malignant cervical lesions. The aims of this study were (1) to assess the number of cervical cells with chromosome 1 aneusomy (monosomy, trisomy, and tetrasomy) in 20 women with cervical intraepithelial neoplasia (CIN 1, CIN 2, CIN 3, and invasive cancer) and three women without CIN by fluorescence in situ hybridization (FISH), (2) to determine the heterogeneity of aneusomy among women within each of the five groups studied, (3) to determine the association between the four progressive stages of cervical cancer and the number of cells with and without aneusomy, (4) to determine the association between number of cells with and without aneusomy and human papilloma virus (HPV) infection, and (5) to determine its usefulness as a biomarker of cancer risk. A hospital-based unmatched case-control study in a sample of 23 women grouped by disease stage and selected by histology from the Obstetrics and Gynecology Hospital of the Instituto Mexicano del Seguro Social (IMSS) in Mexico was conducted in 2002. Numerical aberrations of chromosome 1 in cervical smears were detected with FISH. HPV was detected with polymerase chain reaction (PCR) and typing was performed with restriction fragment length polymorphism (RFLPs). Analysis of chromosome 1 aneusomy revealed (1) homogeneity among women within each one of the five groups, (2) a positive linear trend between the aneusomy frequency and grade of lesion, and (3) an association between aneusomy and high-risk HPV infection. These findings suggest the usefulness of the number of cervical cells with chromosome 1 aneusomy as a biomarker. In order to validate this biomarker we suggest a larger prospective study of cytological samples of patients with a longer follow-up.

Cytopathology. 2005 Feb;16(1):7-12.

Clinical relevance of human papillomavirus testing in cytopathology.

Brink AA, Zielinski GD, Steenbergen RD, Snijders PJ, Meijer CJ. Department of Pathology, Vrij Universiteit Medical Center, Amsterdam, The Netherlands.

Cancer of the uterine cervix is the second most common cancer in women worldwide. Currently, cervical screening is based on cytology alone. Because infection with high-risk human papillomavirus types (hrHPVs) is a necessary cause of cervical cancer, it has been postulated that screening might become more efficient when it is based on combined cytology and hrHPV testing. In this review we will discuss the advantages of added HPV tests in cervical cancer screening, as a quality control for false-negative smears, in triage of women with equivocal smears, in follow-up of women treated for CIN3 or cervical cancer and for the detection of cervical adenocarcinoma.

Anticancer Res. 2005 Mar-Apr;25(2A):765-77.

Activity and therapeutic potential of ORI-1001 antisense oligonucleotide on human papillomavirus replication utilizing a model of dysplastic human epithelium.

Alam S, Bromberg-White J, McLaughlin-Drubin M, Sen E, Bodily JM, Meyers C. Department of Microbiology and Immunology, The Pennsylvania State University, College of Medicine, Hershey, PA 17033, USA.

Human Papillomaviruses (HPVs) are small double-stranded DNA viruses that infect the cutaneous or mucosal epithelium. The high-risk genital HPVs are associated with squamous intraepithelial lesions of the anogenital region that can progress to cancer. Cervical cancer is the third leading cause of cancer death in women worldwide, yet there are no specific therapeutic treatments for HPV-associated malignancies. Development of specific antisense oligonucleotides as antiviral agents is an alternative therapeutic strategy. We utilized the organotypic raft culture system which recapitulates the entire HPV life cycle, including the production of infectious virions. We studied the effect of the ORI-1001 antisense phosphorothioate oligonucleotide designed against the E1 mRNA translation start site of low-risk HPV6 and HPV11, and tested it against high-risk HPV31b and HPV16 vegetative replication and oncogene promoter activity. ORI-1001 significantly inhibited HPV31b genome amplification. In contrast, HPV16 genome amplification was unaffected. In addition, ORI-1001 significantly downregulated transcriptional activity from a HPV31b p99 early promoter luciferase reporter construct, and inhibited E1 and E6E7 transcript expression from the wild-type genome. Our results support the idea that the antisense activity of OR-1001 can target HPV31b functional activities in the differentiation dependent life cycle of this virus. Our results predict that binding stability between antisense oligonucleotides with partial homology to HPV genes may mediate targeting of multiple HPV types. Our studies also highlight the utility of the raft culture system in defining the parameters for testing antisense oligonucleotides against HPV.

Clin Immunol. 2005 Jun;115(3):295-301.

Integration of high-risk human papillomavirus DNA correlates with HLA genotype aberration and reduced HLA class I molecule expression in human cervical carcinoma.

Sheu BC, Chiou SH, Chang WC, Chow SN, Lin HH, Chen RJ, Huang SC, Ho HN, Hsu SM. Department of Obstetrics and Gynecology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan.

In human cervical cancer (CC), local immunity against this human papilloma virus (HPV)-associated neoplasia has been signified. To stratify the possibility of HPV integration on HLA mutations, we measured the genotypic and phenotypic integrity of all available HLA class I loci in 30 cases of CC. Paired normal and cancer genomic DNA was analyzed with DNA typing trays, including 57 subtypes of HLA-A, 120 subtypes of HLA-B, and 60 subtypes of HLA-C. We demonstrated significant mutations of HLA genotype with reduced HLA molecule expression in CC. HPV coincide in >70% cases of aberrant HLA genes. Southern blot analysis revealed the presence of HPV DNA within the mutated HLA foci. Our study reveals a plausible role of HPV integration in the contexts of aberrant HLA genotypes in CC cells. Disruptions of the HLA genes can be possible tactics of HPV to attain the potential carcinogenetic purposes, and thus the cancer immune escape.

Med Mal Infect. 2005 May 2; [Epub ahead of print]

Ano-genital lesions due to human papillomavirus infection in women.

HPV Virus Medical - Article in French

Human papillomaviruses (HPV) are the most prevalent sexually-transmitted agents worldwide. HPV are small circular double-stranded DNA epitheliotropic viruses that exhibit either cutaneous or mucosal specificity. Most HPV infections are self-limiting and are spontaneously cleared within months or years. However, infections may persist and result in a variety of benign, pre-malignant and malignant tumors. Cytological and histopathological abnormalities associated with HPV infections of the male and female lower anogenital tract include condylomata, low-grade and high-grade squamous intraepithelial lesions which are incipient cancers, and squamous cell carcinomas. The modal time between HPV infection occurring in the late teens or early 20 s and precancer peaking around 30 years of age is 7-10 years. Women detected with invasive cancers tend to be an average 10 years older than women with high-grade disease. The natural history of cervical cancer reveals that infection with high-risk types may lead to low-grade or high-grade intraepithelial lesions. High-grade lesions may progress to cervical carcinoma if not treated. The purpose of screening, in addition to detecting cervical cancers at an early stage, is to detect and remove high-grade lesions and thus prevent the potential progression to cervical carcinoma. Early detection of cervical neoplasia is possible with regular Pap smears performed from 21 to 70 years of age. In case of abnormal Pap smear, a biopsy performed under colposcopy will allow the diagnosis of cervical lesion. Cancer of the cervix is the second leading cause of cancer related deaths among women across the world (3,400 new cases in France in 2000).

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