Human Papilloma Virus

Grm HS, Massimi P, Gammoh N, Banks L. 1International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34012 Trieste, Italy.

Human papillomaviruses are the causative agents of cervical cancer. Previous studies have shown that loss of the viral E2 protein during malignant progression is an important feature of HPV-induced malignancy due to the resulting uncontrolled expression of the viral oncoproteins E6 and E7. We now show however that the viral E2 and E6 proteins are both capable of regulating each other's activity. When coexpressed, E2 and E6 induce marked changes in the pattern of each other's expression, with preferential accumulation in nuclear speckles. The two proteins interact directly, resulting in changes in the substrate specificities of E6 and the biochemical activities of E2. Thus, while E6 efficiently degrades its PDZ domain-containing substrates in the absence of E2, this activity is greatly diminished when E2 is present. Likewise, E2 alone drives both viral DNA replication and viral gene expression. However, in the presence of E6, viral DNA replication is inhibited while the transcriptional activity of E2 is elevated. These studies define a far more complex pattern of interaction between E2 and E6 than was previously thought and redefines the possible consequences of loss of E2 with respect to uncontrolled E6 activity and consequent malignant progression.Oncogene advance online publication, 25 April 2005; doi:10.1038/sj.onc.1208701.

J Reprod Med. 1989 Aug;34(8 Suppl):566-71.

Papillomavirus and vulvovaginal neoplasia.

Crum CP, Burkett BJ. Department of Pathology, University of Virginia Health Sciences Center, Charlottesville.

Cumulative evidence strongly implicates human papillomavirus (HPV) in the genesis of squamous neoplasia of the lower female genital tract, including the vulva. The association of HPV with neoplasms at that site includes the relationship of specific HPV types with neoplasms and evidence that those HPV DNA types can transform epithelial cells in vitro. The capacity for in vitro transformation has been isolated to specific regions of the HPV genome. That may be unique in cancer-associated viruses. Nevertheless, epidemiologic evidence points to additional factors, including immunologic, habitual and environmental, that may play an important role in the development of lower genital tract carcinomas. In particular, the marked differences in mean age and other variables between women with vulvar precancers and invasive cancer suggest that the evolution of invasive cancer involves more than HPV infection alone. Hence, the prevention of invasive vulvar cancer in older age groups will require an understanding of the unique host factors that render a small group of women susceptible to the disease in the face of an epidemic of HPV infection in the population at large.

Publication Types:
• Review
• Review, Multicase

Sex Transm Infect. 2005 Apr;81(2):128-32.

Biological and hormonal markers of chlamydia, human papillomavirus, and bacterial vaginosis among adolescents attending genitourinary medicine clinics.

Brabin L, Fairbrother E, Mandal D, Roberts SA, Higgins SP, Chandiok S, Wood P, Barnard G, Kitchener HC. Academic Unit of Obstetrics and Gynaecology and Reproductive Health Care, Research Floor, St Mary's Hospital, Whitworth Park, Manchester M13 0JH, UK.

OBJECTIVE: To assess maturity indices, menstrual patterns, hormonal factors, and risk of adolescent genital tract infections. METHODS: Cross sectional study in three genitourinary medicine clinics. Females 17 years or less, within 5 years of menarche, or reporting oligo-amenorrhoea were screened for genital tract infections and menstrual cycle characteristics determined. The outcome measures were risk factors associated with chlamydia, human papillomavirus (HPV DNA) and bacterial vaginosis (BV), separately and pooled. Correlations between estrone-3-glucuronide (E3G) and pregnanediol-3alpha-glucuronide (P3G) hormone concentrations and chlamydia, HPV, and BV. RESULTS: Among 127 adolescents, HPV was present in 64.4% (95% CI: 54.5 to 74.3), BV in 33.9% (19.1 to 34.5), and chlamydia in 26.8% (19.1 to 34.5). Breast maturity, oligomenorrhoea, and older gynaecological age were associated with lower risk of all infections. After adjustment for calendar age, race, and behavioural factors, gynaecological age remained significant (OR = 0.7, 0.6-0.9; p = 0.008). Behavioural risk factors differed by infection. Smoking was protective for HPV (OR = 0.1, 0.0 to 0.9; p = 0.007), and a recent new partner for chlamydia (OR = 0.3, 0.1 to 0.9; p = 0.024). Sex during menses was associated with increased BV risk (OR = 3.3, 1.5 to 7.2; p = 0.003). Chlamydia was higher among adolescents who used emergency contraception (2.5; 1.1 to 5.9, p = 0.029) and lower among those using condoms at last sex (OR = 0.3, 0.1 to 0.9; p = 0.015). Among 25 adolescents not using hormonal contraceptives, 15 had disturbed or anovulatory cycles. Chlamydia risk was inversely associated with P3G concentrations (Mann-Whitney; p = 0.05). CONCLUSIONS: Adolescents engaging in high risk behaviour at a young gynaecological age are susceptible to multiple infections. Adolescent clinical assessment should include gynaecological age.

Publication Types:
• Multicenter Study

Cleve Clin J Med. 2005 Feb;72(2):141-8.

Comment in:

New cervical cancer screening strategy: combined Pap and HPV testing.

Jin XW, Zanotti K, Yen-Lieberman B. Department of General Internal Medicine, The Cleveland Clinic Foundation, OH 44195, USA. jinx@ccf.org

Our strategy for cervical cancer screeing is being revolutionized by our new understanding of how human papillomavirus (HPV) contributes to carcinogenesis and the natural history of cervical cancer. The American Cancer Society and the American College of Obstetricians and Gynecologists now recommend combined HPV and Papanicolaou (Pap) testing for cervical cancer screening in women age 30 or older. However, although incorporation of HPV DNA testing into primary screening provides clear benefits, it also raises new questions.

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.

J Clin Virol. 2005 Mar;32 Suppl 1:S25-33.

HPV-mediated transformation of the anogenital tract.

Steenbergen RD, de Wilde J, Wilting SM, Brink AA, Snijders PJ, Meijer CJ. Department of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. r.steenbergen@vumc.nl

Infection with high-risk human papillomavirus (HR-HPV) has been associated with intraepithelial neoplasia and carcinomas at various sites of the anogenital tract, including the cervix, vulva, vagina, penis and anus. Although HR-HPV is a necessary cause for cervical cancer, the majority of anal cancers and a subset of cancers at other genital sites, additional (epi)genetic events are required for malignant transformation. HPV-mediated transformation of human epithelial cells has been recognized as a multi-step process resulting from deregulated transcription of the viral oncogenes E6 and E7 in the proliferating cells. Interference of E6 and E7 with cell cycle regulators induces genetic instability, which drives the continuous selection of oncogenic alterations providing cells with a malignant phenotype. Early genetic events during cervical carcinogenesis associated with immortalization, include deletions at chromosomes 3p, 6 and 10p, whereas amongst others gain of chromosome 3q, loss of chromosome 11 and epigenetic alterations such as inactivation of the TSLC1 tumor suppressor gene represent later events associated with tumor invasion.

Human Papilloma Virus - HPV Research Links

Fact Sheet on HPV and Dysplasia - From the Rutgers Health Clinic, this is the sheet they give to women who have a positive Pap test. Has good info about both HPV and cervical dysplasia.

HPV and Pelvic Exam - A pelvic exam will include a Pap smear, but is much more than that. Regular pelvic exams are first-line cancer screening for almost all gyn cancers.