Human Papilloma Virus - HPV - Research

del Refugio Gonzalez-Losa M, Laviada Mier y Teran MA, Puerto-Solis M, Garcia-Carranca A. Virology Laboratory, Regional Research Center Dr Hideyo Noguchi, Autonomous University of Yucatan, Merida, Yucatan, Mexico.

BACKGROUND: Cervical cancer is the second most common cancer in women worldwide. Infection with human papillomavirus (HPV) 16 is an important risk factor associated with cervical cancer, more than 50% of cervical cancer tissues have DNA of HPV 16. Intratypic variants have been reported, although they differ in prevalence, biological and biochemical properties, their implication in the aetiology of cervical cancer is still uncertain. OBJECTIVE: To identify HPV type 16 E6 variants among Mexican women with diagnosis of low-grade squamous intraepithelial lesion (LSIL) or invasive cancer (IC). STUDY DESIGN: Forty HPV16-positive samples were included, 15 were from women with LSIL, 25 from women with IC; 610 pb from the E6 gene were amplified by PCR and the variant status subsequently determined by hybridization with 27 biotinilated probes. Statistical analysis was performed with chi2, odds ratio (OR). RESULTS: In the LSIL group we only found ten (66%) EP and five (33%) EP350G variants. In the IC group, four variants were found; 11 (44%) AA, seven (28%) EP, six (24%) EP350G, one (4%) Af2. Comparison of the frequency of variants differed from EP in both groups of patients (P=0.01) with an odds ratio (OR) of 5.14 (CI 95% [1.07-26.56]). CONCLUSION: This study demonstrates an association between HPV type 16 variants different from prototype (EP) and invasive cervical cancer.

Gynecol Oncol. 2004 Mar;92(3):873-80.

Physical state and expression of HPV DNA in benign and dysplastic cervical tissue: different levels of viral integration are correlated with lesion grade.

Hudelist G, Manavi M, Pischinger KI, Watkins-Riedel T, Singer CF, Kubista E, Czerwenka KF. Department of Gynecology and Obstetrics, Division of Special Gynecology, University of Vienna Medical Center, Vienna, Austria.

OBJECTIVE: Human papillomavirus (HPV) infection is the most important event in the malignant transformation of human cervical epithelium. Several high-risk (HR-)HPV subtypes have been identified, which lead to CIN and subsequently to invasive carcinoma. The reason for this phenomenon is still unknown, but it seems to be related to the physical state of HPV DNA. METHODS: Digene HC II test was used to identify HR- and/or low-risk (LR-)HPV infections in cervical swabs of 275 women attending our clinic for routine cytological screening and/or colposcopy because of an abnormal Pap smear comprising low-grade squamous intraepithelial lesions (LGSIL) and high-grade SIL (HGSIL). Specific HR (16, 18, 31, 33, 52b, 58) and LR (6, 11) subtypes were characterized in cervical biopsies of 10 women with benign cellular changes and of 68 women with CIN I-III by the PCR-restriction enzyme method. The physical state of HPV DNA (episomal, mixed and integrated form) was analyzed by bi-dimensional (2D)-gel electrophoresis. In addition, mRNA expression of E6/E7 genes was analyzed by RT-PCR. Furthermore, the relative virus load was determined in nine selected cases. The physical state and transcriptional activity of HPV DNA were then correlated to histopathological results. RESULTS: LR-HPV infection [27 cases (9.8%)] and HR-HPV infection [121 cases (44%)] of cervical swabs were clearly correlated to the degree of SIL. Further HPV typing in cervical biopsies of 78 women showed that HPV6 and 11 were restricted to benign cellular changes, CIN I and II, whereas HPV16 and 18 were observed predominantly in CIN III/CIS (P=0.01). No clear distribution pattern was observed for HPV31, 33, 52b and 58. Expression of HPV E6 and E7 transcripts was uniformly correlated with the different physical state of HPV DNA. Analyzing the physical state of these HPV subtypes, HPV6 and 11 could only be detected as an episomal form, independent of SIL grade. In normal epithelium and in CIN I and II, HPV16 and 18 were exclusively found in the episomal form. In CIN III/CIS, 15 of 30 cases of HPV16 (50%) and 16 of 17 cases of HPV18 (94%) were exclusively integrated into the host genome. Like HPV16/18, HPV31, 33, 52b and 58 were also present in the episomal form in normal epithelium and in CIN I and II, but were integrated in 80% of the CIN III/CIS (4/5) cases. CONCLUSION: Absent integration of HPV16 DNA in some CIN III/CIS suggests that integration is not always required for progression early dysplastic lesions. In contrast, integration of HPV type 18 and others appears to be of major importance for the transforming efficacy of cervical dysplasia. The applied method represents a sensitive instrument to assess the physical state of HPV and is useful to predict the progression of disease.

Gynecol Oncol. 2004 Jan;92(1):225-31.

Presence of multiple human papillomavirus types in cervical samples from HIV-infected women.

Levi JE, Fernandes S, Tateno AF, Motta E, Lima LP, Eluf-Neto J, Pannuti CS. Departamento de Doencas Infecciosas e Parasitarias, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo SP, Brazil.

OBJECTIVES: The aim of this study was to detect and identify human papillomavirus (HPV) genotypes on a population of women infected by the human immunodeficiency virus (HIV) and to investigate the role of multiple infections on cervical dysplasia. METHODS: Two hundred and fifty-five HIV-infected women were enrolled on a study to evaluate the prevalence of HPV and cervical intra-epithelial neoplasia (CIN). A group of HIV-negative women with confirmed CIN diagnosis was included for comparison. A polymerase chain reaction (PCR)-reverse hybridization method was applied to detect and precisely identify HPV types, specifically multiple infections. RESULTS: On HIV patients, an altered Pap smear confirmed by biopsy was observed on 45 (18%); HPV-DNA prevalence was 87% (223/255), with 45% (116/255) infected by more than two types. In contrast, HPV-DNA was detected in all 36 women of the control group but only 3 were infected by more than two types. Cervical dysplasia was associated with low CD4 counts and elevated high-risk HPV viral load. However, the presence of multiple HPV types did not correlate with the degree of immune suppression or the presence of cervical lesions. CONCLUSIONS: Infection with multiple HPV types is a rather frequent finding on Brazilian HIV-infected women. On this population, concomitant infection with three or more HPV types does not seem to confer an additional risk of cervical dysplasia in comparison to single/double infections, nor to be related to more severe immunesuppresion.

Oncogene. 2003 Sep 11;22(39):7969-80.

The relationship between connexins, gap junctions, tissue architecture and tumour invasion, as studied in a novel in vitro model of HPV-16-associated cervical cancer progression.

Aasen T, Hodgins MB, Edward M, Graham SV. Division of Cancer Sciences and Molecular Pathology, University of Glasgow, Glasgow G12 8QQ, UK.

Disruption of gap junctional intercellular communication (GJIC) and/or connexins (gap junction proteins) is frequently reported in malignant cell lines and tumours. Certain human papillomaviruses (HPV) associated with the development of cancers, especially of the cervix, have previously been reported to downregulate GJIC in vitro. There is also evidence for reduced gap junctions in cervical dysplasia. However, many squamous hyperproliferative conditions, including HPV-induced warts, often show extensive upregulation of certain connexins. The association between HPV and GJIC, and the mechanism and consequence of deregulated GJIC in cervical tumour progression, remains unclear. Therefore, using a variety of nonmalignant and malignant cell lines and an organotypic raft-culture system, we investigated the relationship between HPV, gap junctions and tumour progression. Established cervical tumour cell lines carrying HPV were unable to communicate via gap junctions (when assayed by dye-transfer techniques). This correlated with lack of connexin protein expression, while transfection with connexins 26 or 43 led to functional gap junction membrane plaques. On the other hand, immortal but nonmalignant cell lines that contained episomal or integrated HPV-16, but required feeder-layer and growth-factor support, were consistently well coupled, and expressed multiple connexins at membrane junctions. In vitro selection of feeder-layer and growth-factor-independent variants eventually lead to loss of GJIC, which correlated with loss of membrane and increased cytoplasmic connexin 43 localization. However, this was preceded by loss of differentiation and stromal invasion, as assayed on the organotypic raft-culture model. Using this model, a comparison between noncoupled, well-coupled and connexin-transfected cell lines revealed no firm correlation between GJIC and dysplasia, but GJIC appeared to favour increased stratification. These findings demonstrate that loss of GJIC is frequent, but appears to occur more as a consequence of, rather than being the cause of, epithelial dysplasia, and may be influenced by, but is not directly attributable to, HPV.

Nutrition. 2003 Jun;19(6):497-502.

Folate, vitamin B12, and homocysteine status. findings of no relation between human papillomavirus persistence and cervical dysplasia.

Sedjo RL, Fowler BM, Schneider A, Henning SM, Hatch K, Giuliano AR. Arizona Cancer Center, 1515 N. Campbell Avenue, Room 4977 C, Phoenix, AZ 85724-5024, USA.

OBJECTIVES: Human papillomavirus (HPV) infections are the cause of most, if not all, cervical cancers. Women consistently positive for oncogenic type HPV infections have a greater risk of developing cervical dysplasia compared with women transiently infected. HPV infection alone appears to be insufficient to produce disease, suggesting that other cofactors may be needed. Folate, vitamin B12, and homocysteine, through their role in DNA methylation, may be involved in cervical neoplasia. METHODS: This study examined the associations between HPV persistence and circulating folate, vitamin B12, and homocysteine levels among 91 low-income Hispanic women. Further, the relation of these nutrients to cervical pathology was evaluated. HPV status was determined at two visits approximately 3 mo apart. RESULTS: Adjusted mean circulating concentrations of folate, vitamin B12, and homocysteine were not statistically different between women with two positive HPV tests, one positive test, or two negative HPV tests. No association was observed between tertiles of folate, vitamin B12, or homocysteine and HPV persistence risk. Further, adjusted mean levels of these nutrients were not statistically different between cytologic grades. CONCLUSIONS: Results from this small study did not support a role for folate, vitamin B12, or homocysteine in HPV persistence or cervical dysplasia.

hpv human papilloma viruses - HPV Research Links

American Social Health Association - Learn scientific facts and read about various methods of screening and treating HPV, including information on the vaccine for HPV.

National Cancer Institute - Information on all kinds of cancer, including HPV-related cases in one place.