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Molecular diagnosis of human papillomaviruses (HPVs) in cervicovaginal samples reveals a plethora of known and novel HPV genomes. We describe the use of an overlapping PCR method to clone and analyze the complete genome of HPV 84 from cervicovaginal cells obtained from a 21-year-old Caucasian female with a normal Pap smear. The 7948-bp complete nucleotide sequence of HPV 84 was determined from five...
The E1 and E2 proteins encoded by papillomaviruses are required for viral replication. Earlier studies have shown that the viral E2 protein plays an important role in replication by targeting the E1 helicase to the origin of replication (ori). We have previously shown that the E1 protein of human papillomavirus (HPV) type 1 is sufficient for the in vivo replication of ori plasmids, although the E2...
Human papillomavirus type 18 is a causative agent of epithelial cancers in the uterine cervix. We show here that estrogen and progesterone activate β-galactosidase expression from the early promoter of this virus in the genital epithelia of transgenic mice. Ovariectomy caused suppression of transgene expression exclusively in vagina and cervix epithelia. β-Galactosidase expression could be restored...
Inhibitors of histone deacetylase (HDAC) are capable of arresting growth in cervical carcinoma cells in the G1 phase of the cell cycle. Although HPV E6/E7 mRNA steady-state levels appeared to be constant after prolonged treatment, time-course experiments revealed that viral transcription was transiently down-regulated between 7–10 h prior to cdk2 suppression. To test whether transitory suppression...
Recent epidemiological studies have found that women infected with both herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) type 16 or HPV-18 are at greater risk of developing cervical carcinoma compared to women infected with only one virus. However, it remains unclear if HSV-2 is a cofactor for cervical cancer or if HPV and HSV-2 interact in any way. We have studied the effect of...
Studies on the presence of human papillomavirus (HPV) DNA in cervical samples show that 10% or more of all clinical lesions contain at least two different HPV types. We have investigated if multiple HPV types can exist in the same cell and interact with one another or if they merely exist in the same tissue. Combinations of genital HPV genomes were electroporated into primary keratinocytes. Southern...
With the goal of identifying genes with a differential pattern of expression between invasive cervical carcinomas (CVX) and normal cervical keratinocytes (NCK), we used oligonucleotide microarrays to interrogate the expression of 14,500 known genes in 11 primary HPV16 and HPV18-infected stage IB–IIA cervical cancers and four primary normal cervical keratinocyte cultures. Hierarchical cluster analysis...
The study of the human papillomavirus (HPV) life cycle was hampered for more than 50 years by the lack of a conventional cell culture system for propagating HPV. Considerable progress has been made in the production of several HPV types using either organotypic rafts or human epithelial xenografts in immunocompromised mice. In this study, we demonstrated episomal maintenance of HPV-11 DNA in N-Tert...
Infection by high-risk human papillomaviruses (HPV) and persistent expression of the viral oncogenes E6 and E7 are causally linked to the development of cervical cancers. These oncogenes require additional events for the complete transformation of human epithelial cells. Although exaggerated levels of c-Myc are observed in many cases of cervical cancer, the actual function of c-Myc in the process...
Human papillomavirus (HPV) is known as a strictly epitheliotropic pathogen. Our results raised the possibility that HPV 16 is present in neural cells and in the vascular endothelium. By in situ hybridization, we have detected HPV 16 E6 ORF sequence in small blood vessels and peripheral nerves adjacent to oral and cervical cancers. The same structures have clearly shown immunohistochemical reactivity...
Human papillomavirus type 16 (HPV-16) E2 protein negatively regulates transcription of the E6 and E7 genes. This study was done to test the hypothesis that methylation of the HPV 16 long control region (LCR) is overrepresented among cervical cancer (CaCx) cases compared to cytologically normal controls harboring intact E2 gene. Methylation of the E2 binding site (E2BS-I), proximal to the P97 promoter,...
The cellular E3 ubiquitin ligase E6AP (UBE3A) interacts with the cancer-associated HPV E6 oncoproteins, where together with the viral E6 oncoprotein it binds and targets the degradation of the p53 tumor suppressor. We find that the HPV-11E6 protein also associates with E6AP in vivo, and thereby can target the degradation of an E6-associated protein. Mutation of an E6-binding LXXLL peptide motif on...
Epidemiological studies have demonstrated that 15 different mucosal human papillomavirus (HPV) types of the genus alpha of the HPV phylogetic tree are classified as high risk for cervical cancer development. Three additional HPV types of the same genus, HPV26, 53 and 66, are classified as probable high-risk types. In this study, we have characterized the biological properties of the E7 oncoproteins...
Human papillomavirus type 16 (HPV-16) infections can in rare cases persist and cause lesions that may progress to cervical cancer. Cells in the lesions are not permissive for virus production, nor are cervical cancer cells. The intracellular environment is such that it prevents production of the highly immunogenic, viral structural proteins L1 and L2. One may speculate that inhibition of L1 and L2...
We re-sequenced HPV16 genome (~6 kb) implicated in cervical carcinogenesis (LCR, E2, E5, E6, E7, L1, L2) to prioritize sequence variants for functional validation as biomarkers, using CaCx cases (n=74) and asymptomatic controls (n=24). Of the nucleotide variations recorded (n=271), non-synonymous changes in L2 region were significantly higher (p=0.005) among cases (2.67%) compared to controls (1.27%)...
High-risk human papillomaviruses (HPV) cause cervical cancer. The biological properties of HPV-45, the third most prevalent high-risk HPV-genotype, are unknown. We demonstrate here that the HPV-45 E7 protein transforms immortalized NIH3T3 fibroblasts, while mutations in either the conserved LXCXE sequence (C28G) or the carboxyl-terminus (Δ87LQQLF91) significantly abolish this activity. To address...
Human papillomaviruses (HPV) 16 is a DNA virus encoding three oncogenes — E5, E6, and E7. The E6 and E7 proteins have well-established roles as inhibitors of tumor suppression, but the contribution of E5 to malignant transformation is controversial. Using spontaneously immortalized human keratinocytes (HaCaT cells), we demonstrate that expression of HPV16 E5 is necessary and sufficient for the formation...
Human papillomaviruses (HPV) are small DNA viruses that contain a compact and non-redundant genome. HPV, with the help of only few genes, can achieve a complete vegetative cycle specifically in the epidermal and mucosal keratinocytes. Modification of the host cell transcriptional regulation is one of the major ways to regulate the viral production and maturation. The vegetative cycle of papillomaviruses...
Approximately 35 years ago a role of human papillomaviruses (HPV) in cervical cancer has been postulated. Today it is well established that this very heterogeneous virus family harbours important human carcinogens, causing not only the vast majority of cervical, but also a substantial proportion of other anogenital and head and neck cancers. In addition, specific types have been linked to certain...
There is compelling evidence that high-risk human papillomaviruses (HPV) can cause cervical cancer. Strikingly, HPV16 and 18 account for ∼70% of all cervical cancers, whereas phylogenetically related types are found at much lower frequencies. Most likely, differences in the activities of the viral E6 and E7 oncoproteins account for the in vivo carcinogenicity. We demonstrate here that E6 proteins...
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