scholarly journals Induction of the Upstream Regulatory Region of Human Papillomavirus Type 31 by Dexamethasone Is Differentiation Dependent

2003 ◽  
Vol 77 (20) ◽  
pp. 10975-10983 ◽  
Author(s):  
Jennifer L. Bromberg-White ◽  
Ellora Sen ◽  
Samina Alam ◽  
Jason M. Bodily ◽  
Craig Meyers
Keyword(s):  
Life Cycle ◽  
Monolayer Culture ◽  
Regulatory Region ◽  
Hpv Infection ◽  
Human Papillomaviruses ◽  
Host Tissue ◽  
Semisolid Medium ◽  
Glucocorticoid Response ◽  
Hpv Types ◽  
Glucocorticoid Response Elements

ABSTRACT Glucocorticoids have been shown to play a role in the transforming abilities of human papillomaviruses (HPVs), and glucocorticoid response elements (GREs) have been identified in the upstream regulatory regions (URRs) of various HPV types. These findings have made glucocorticoids potential therapeutic targets for HPV infection. We have previously shown that the URR of HPV type 31 (HPV31) is insensitive to induction by the synthetic glucocorticoid dexamethasone (dex) in monolayer culture, despite the identification of three potential GREs in the 5′ region of the URR. Due to the fact that the HPV life cycle is intimately linked to the differentiation of the host tissue, we chose to determine whether the URR of HPV31 was inducible by dex under differentiating conditions. Upon suspension of cells in a semisolid medium of methylcellulose, we found that the URR of HPV31 was inducible by dex. The three GREs appear to play roles as independent repressors of this inducibility. By 5′ deletion analysis, the element(s) responsible for this induction was localized to nucleotides (nt) 7238 to 7557. Furthermore, we found that the region between nt 7883 and 7900 appears to act as a repressor of dex inducibility. These findings indicate that epithelial differentiation has a profound effect on the action of dex on the URR of HPV31, suggesting that glucocorticoids play an important role in the differentiation-dependent life cycle of HPV.

scholarly journals The Upstream Regulatory Region of Human Papillomavirus Type 31 Is Insensitive to Glucocorticoid Induction

2002 ◽  
Vol 76 (19) ◽  
pp. 9702-9715 ◽  
Author(s):  
Jennifer L. Bromberg-White ◽  
Craig Meyers
Keyword(s):  
Transcriptional Activation ◽  
Regulatory Region ◽  
Human Papillomaviruses ◽  
Upstream Regulatory Region ◽  
Oncogenic Potential ◽  
Shift Analysis ◽  
Glucocorticoid Response ◽  
Glucocorticoid Induction ◽  
Glucocorticoid Response Elements

ABSTRACT The upstream regulatory region (URR) of various types of human papillomaviruses (HPVs) has been shown to contain functional glucocorticoid response elements (GREs), including HPV type 11 (HPV11), HPV16, and HPV18. Glucocorticoids have been demonstrated to induce the transcriptional activity of the early promoters of these HPV types. Although it has been assumed that the URR of HPV31 contains at least one GRE, no functionality has been demonstrated. We attempt to show here inducibility of the URR of HPV31 by the synthetic glucocorticoid dexamethasone (dex). By sequence analysis we identified three potential GREs in the URR of HPV31. Gel shift analysis indicated that each of these three sites has the potential to be a functional GRE. However, constructs containing the full-length URR, 5′ deletions of the URR, and an internal fragment of the URR containing all three putative GREs were only weakly inducible by dex. Linker scanning mutants, whereby each potential GRE was replaced individually, in double combination, or in triple combination by a unique polylinker, had no effect on dex inducibility. Replacement of each of the three HPV31 GREs with the GRE of HPV18 failed to induce a response to dex. Placement of the HPV18 GRE into the URR of HPV31 in a region similar to its location in the HPV18 URR was also unable to result in a strong dex induction of the HPV31 URR. These data suggest that the lack of dex inducibility is due to the overall context of the HPV31 URR and may be dependent on the requirements of the major early promoter for transcriptional activation. Finally, replacement of the HPV18 GRE with each of the HPV31 GREs in HPV18 only showed weak inducibility, indicating that the three GREs of HPV31 are in fact only weak inducers of dex. Overall, these data suggest that dex responsiveness, along with oncogenic potential, may provide a possible explanation for the classification of HPV31 as an intermediate-risk virus and demonstrate the complexity of transcriptional regulation of the URR of HPV.

scholarly journals Pathogenesis of Human Papillomaviruses in Differentiating Epithelia

2004 ◽  
Vol 68 (2) ◽  
pp. 362-372 ◽  
Author(s):  
Michelle S. Longworth ◽  
Laimonis A. Laimins
Keyword(s):  
Life Cycle ◽  
Genital Tract ◽  
Basal Layer ◽  
Viral Life Cycle ◽  
Human Papillomaviruses ◽  
Basal Cells ◽  
Human Pathogens ◽  
Late Gene Expression ◽  
Differentiated Cells ◽  
Hpv Types

SUMMARY Human papillomaviruses (HPV) are the etiological agents of cervical and other anogenital malignancies. Over 100 different types of HPVs have been identified to date, and all target epithelial tissues for infection. One-third of HPV types specifically infect the genital tract, and a subset of these are the causative agents of anogenital cancers. Other HPV types that infect the genital tract induce benign hyperproliferative lesions or genital warts. The productive life cycle of HPVs is linked to epithelial differentiation. Papillomaviruses are thought to infect cells in the basal layer of stratified epithelia and establish their genomes as multicopy nuclear episomes. In these cells, viral DNA is replicated along with cellular chromosomes. Following cell division, one of the daughter cells migrates away from the basal layer and undergoes differentiation. In highly differentiated suprabasal cells, vegetative viral replication and late-gene expression are activated, resulting in the generation of progeny virions. Since virion production is restricted to differentiated cells, infected basal cells can persist for up to several decades or until the immune system clears the infection. The E6 and E7 genes encode viral oncoproteins that target Rb and p53, respectively. During the viral life cycle, these proteins facilitate stable maintenance of episomes and stimulate differentiated cells to reenter the S phase. The E1 and E2 proteins act as origin recognition factors as well as regulators of early viral transcription. The functions of the E5 and E1^E4 proteins are still largely unknown, but these proteins have been implicated in modulating late viral functions. The L1 and L2 proteins form icosahedral capsids for progeny virion generation. The characterization of the cellular targets of these viral proteins and the mechanisms regulating the differentiation-dependent viral life cycle remain active areas for the study of these important human pathogens.

scholarly journals Epigenetic Regulation of the Human Papillomavirus Life Cycle

Pathogens ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 483 ◽  
Author(s):  
Michelle Mac ◽  
Cary A. Moody
Keyword(s):  
Life Cycle ◽  
Hpv Infection ◽  
Epigenetic Modifications ◽  
Human Papillomaviruses ◽  
Epigenetic Changes ◽  
Epigenetic Alterations ◽  
Malignant Phenotype ◽  
Public Health Burden ◽  
Damage Response

Persistent infection with certain types of human papillomaviruses (HPVs), termed high risk, presents a public health burden due to their association with multiple human cancers, including cervical cancer and an increasing number of head and neck cancers. Despite the development of prophylactic vaccines, the incidence of HPV-associated cancers remains high. In addition, no vaccine has yet been licensed for therapeutic use against pre-existing HPV infections and HPV-associated diseases. Although persistent HPV infection is the major risk factor for cancer development, additional genetic and epigenetic alterations are required for progression to the malignant phenotype. Unlike genetic mutations, the reversibility of epigenetic modifications makes epigenetic regulators ideal therapeutic targets for cancer therapy. This review article will highlight the recent advances in the understanding of epigenetic modifications associated with HPV infections, with a particular focus on the role of these epigenetic changes during different stages of the HPV life cycle that are closely associated with activation of DNA damage response pathways.

scholarly journals Broad Neutralization Responses Against Oncogenic Human Papillomaviruses Induced by a Minor Capsid L2 Polytope Genetically Incorporated Into Bacterial Ferritin Nanoparticles

2020 ◽  
Vol 11 ◽  
Author(s):  
Fan Yang ◽  
Filipe C. Mariz ◽  
Xueer Zhao ◽  
Gloria Spagnoli ◽  
Simone Ottonello ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Capsid Protein ◽  
Pyrococcus Furiosus ◽  
Neutralizing Antibody ◽  
Hpv Infection ◽  
Cross Reactivity ◽  
Human Papillomaviruses ◽  
Promising Alternative ◽  
Peptide Epitope ◽  
Hpv Types

Cervical cancer remains a global health burden despite the introduction of highly effective vaccines for the prophylaxis of causative human papillomavirus infection (HPV). Current efforts to eradicate cervical cancer focus on the development of broadly protective, cost-effective approaches. HPV minor capsid protein L2 is being recognized as a promising alternative to the major capsid protein L1 because of its ability to induce responses against a wider range of different HPV types. However, a major limitation of L2 as a source of cross-neutralizing epitopes is its lower immunogenicity compared to L1 when assembled into VLPs. Various approaches have been proposed to overcome this limitation, we developed and tested ferritin-based bio-nanoparticles displaying tandemly repeated L2 epitopes from eight different HPV types grafted onto the surface of Pyrococcus furiosus thioredoxin (Pf Trx). Genetic fusion of the Pf Trx-L2(8x) module to P. furiosus ferritin (Pf Fe) did not interfere with ferritin self-assembly into an octahedral structure composed by 24 protomers. In guinea pigs and mice, the ferritin super-scaffolded, L2 antigen induced a broadly neutralizing antibody response covering 14 oncogenic and two non-oncogenic HPV types. Immune-responsiveness lasted for at least one year and the resulting antibodies also conferred protection in a cervico-vaginal mouse model of HPV infection. Given the broad organism distribution of thioredoxin and ferritin, we also verified the lack of cross-reactivity of the antibodies elicited against the scaffolds with human thioredoxin or ferritin. Altogether, the results of this study point to P. furiosus ferritin nanoparticles as a robust platform for the construction of peptide-epitope-based HPV vaccines.

scholarly journals High HPV Infection Prevalence in Men from Infertile Couples and Lack of Relationship between Seminal HPV Infection and Sperm Quality

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Barbara Golob ◽  
Mario Poljak ◽  
Ivan Verdenik ◽  
Mojca Kolbezen Simoniti ◽  
Eda Vrtačnik Bokal ◽  
...  
Keyword(s):  
Sperm Quality ◽  
External Genitalia ◽  
Hpv Infection ◽  
Human Papillomaviruses ◽  
Sperm Parameters ◽  
Infection Prevalence ◽  
Hpv Dna ◽  
Abnormal Sperm ◽  
Hpv Types ◽  
Infertile Couples

Human papillomaviruses (HPV) are the most frequently sexually transmitted viruses and etiological agents of several human cancers. Controversial results of the role of HPV in infertile population on sperm parameters have been published. The aim of this study was to estimate the type-specific prevalence of HPV DNA infection of the external genitalia and semen in 340 Slovenian men from infertile couples and to establish the relationship between seminal HPV DNA infection and abnormal sperm parameters. Self-taken swabs of the entire penile surface and semen samples were collected, and HPV detection and genotyping were performed. HPV DNA was detected in 37.12% of external genitalia and in 13.61% of semen samples with high HPV type concordance of both sampling sites. The most prevalent HPV types in the male external genitalia were HPV-CP6108 and HPV-84. The most prevalent HPV types in semen were HPV-53 and HPV-CP6108. The prevalence of HPV infection between normozoospermic men and men with abnormal sperm parameters did not differ significantly. Sperm quality did not differ significantly between men with seminal HPV infection and uninfected men. In conclusion, the men from infertile couples are equally susceptible to HPV infection regardless of their fertile potential; seminal HPV infection does not impair sperm quality.

scholarly journals Cross-talk of cutaneous beta human papillomaviruses and the immune system: determinants of disease penetrance

2019 ◽  
Vol 374 (1773) ◽  
pp. 20180287 ◽  
Author(s):  
Assunta Venuti ◽  
Stefan Lohse ◽  
Massimo Tommasino ◽  
Sigrun Smola
Keyword(s):  
Immune System ◽  
Cross Talk ◽  
Genetic Disorder ◽  
Hpv Infection ◽  
Human Papillomaviruses ◽  
Skin Carcinogenesis ◽  
Anogenital Region ◽  
Disease Penetrance ◽  
Hpv Types ◽  
Mucosal Hpvs

Human papillomaviruses (HPVs) infect the epithelia of skin or mucosa, where they can induce hyperproliferative lesions. More than 220 different HPV types have been characterized and classified into five different genera. Mucosal high-risk HPVs are causative for cancers of the anogenital region and oropharynx. Clinical data from patients with the rare genetic disorder epidermodysplasia verruciformis (EV) indicate that genus beta-HPVs cooperate with ultraviolet (UV) radiation in the development of cutaneous squamous cell carcinoma. In addition, epidemiological and biological findings indicate that beta-HPV types play a role in UV-mediated skin carcinogenesis also in non-EV individuals. However, the mechanisms used by these cutaneous viruses to promote epithelial carcinogenesis differ significantly from those of mucosal HPVs. Recent studies point to a delicate cross-talk of beta-HPVs with the cell-autonomous immunity of the host keratinocytes and the local immune microenvironment that eventually determines the fate of cutaneous HPV infection and the penetrance of disease. This review gives an overview of the critical interactions of genus beta-HPVs with the local immune system that allow the virus to complete its life cycle, to escape from extrinsic immunity, and eventually to cause chronic inflammation contributing to skin carcinogenesis. This article is part of the theme issue ‘Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses’.

scholarly journals Role of the E1∧E4 Protein in the Differentiation-Dependent Life Cycle of Human Papillomavirus Type 31

2005 ◽  
Vol 79 (11) ◽  
pp. 6732-6740 ◽  
Author(s):  
Regina Wilson ◽  
Frauke Fehrmann ◽  
Laimonis A. Laimins
Keyword(s):  
Life Cycle ◽  
Stop Codon ◽  
S Phase ◽  
Human Papillomaviruses ◽  
Wild Type ◽  
Late Gene Expression ◽  
Semisolid Medium ◽  
Genome Amplification ◽  
Reading Frame

ABSTRACT The most highly expressed protein in the productive life cycle of human papillomaviruses (HPVs) is E1∧E4, but its function is not well understood. To investigate the role of E1∧E4, we undertook a genetic analysis in the context of the complete HPV type 31 (HPV31) genome. A mutant HPV31 genome (E4M9) was constructed that contained a stop codon in the E4 open reading frame at amino acid 9 and was silent in the overlapping E2 coding sequence. Wild-type and mutant genomes were transfected into normal human foreskin keratinocytes (HFKs) and selected for drug resistance, and pooled cultures were examined for effects of E1∧E4 on viral functions. Southern blot analyses of transfected HFKs demonstrated that cells carrying the E4M9 mutant genomes were maintained as episomes at copy numbers similar to those in keratinocytes transfected with wild-type HPV31. Both sets of cells grew at similar rates, exhibited comparable extensions of life spans, and had equivalent levels of early transcripts. Following suspension of the cells in a semisolid medium, differentiation-dependent genome amplification and late gene expression were significantly decreased in cells maintaining the E4M9 mutant genome compared to those with wild-type HPV31. One explanation for these effects could be a reduction in the number of cells harboring mutant genomes that enter S phase upon differentiation. An analysis of cells containing E4M9 mutant genomes in organotypic raft cultures indicated a reduction in bromodeoxyuridine incorporation in differentiated suprabasal cells compared to that seen in wild-type rafts. Our results indicate that the HPV31 E1∧E4 protein plays a significant role in promoting HPV genome amplification and S phase maintenance during differentiation.

scholarly journals Cyclic AMP-dependent protein kinase exhibits antagonistic effects on the replication efficiency of different HPV types

2021 ◽  
Author(s):  
Elina Lototskaja ◽  
Olga Sahharov ◽  
Marko Piirsoo ◽  
Martin Kala ◽  
Mart Ustav ◽  
...  
Keyword(s):  
Life Cycle ◽  
High Risk ◽  
Protein Kinase ◽  
Cyclic Amp ◽  
Protein Kinase A ◽  
Human Papillomaviruses ◽  
Dependent Protein Kinase ◽  
Dependent Protein ◽  
Hpv Types ◽  
Kinase A

Several types of widespread human papillomaviruses (HPVs) may induce transformation of infected cells, provoking the development of neoplasms. Two main genera of HPVs are classified as mucosatropic α and cutaneotropic β HPVs, and they both include high-risk cancer-associated species. The absence of antiviral drugs has driven investigations into the details of the molecular mechanisms of the HPV life cycle. HPV replication depends on viral helicase E1 and transcription factor E2. Their biological activities are controlled by numerous cellular proteins, including protein kinases. Here, we report that ubiquitously expressed cyclic AMP-dependent protein kinase A (PKA) differentially regulates the replication of α HPV11, α HPV18 and β HPV5. PKA stimulates the replication of both α HPVs studied but has a more profound effect on the replication of high-risk α HPV18. However, replication of β HPV5 is inhibited by activated PKA in human primary keratinocytes and U2OS cells. We show that activation of PKA signaling by different pharmacological agents induces rapid proteasomal degradation of the HPV5 E2 protein, which in turn leads to the downregulation of E2-dependent transcription. In contrast, PKA-stimulated induction of HPV18 replication is the result of the downregulation of the E8^E2 transcript coding a potent viral transcriptional inhibitor together with rapid upregulation of E1 and E2 protein levels. IMPORTANCE Several types of human papillomaviruses (HPVs) are causative agents of various types of epithelial cancers. Here, we report that ubiquitously expressed cyclic AMP-dependent protein kinase A (PKA) differentially regulates the replication of various types of HPVs during the initial amplification and maintenance phases of the viral life cycle. Replication of the skin cancer-related pathogen HPV5 is suppressed, whereas replication of the cervical cancer-associated HPV18 is activated in response to elevated PKA activity. To inhibit HPV5 replication, PKA targets the viral transcriptional activator E2, inducing its rapid proteasomal degradation. PKA-dependent stimulation of HPV18 replication relies on the downregulation of another E2 gene product, E8^E2, which encodes a potent transcriptional repressor. Our findings highlight, for the first time, protein kinase-related mechanistic differences in the regulation of the replication of mucosal and cutaneous HPV types.

scholarly journals The Laboratory Diagnosis of Genital Human Papillomavirus Infections

2005 ◽  
Vol 16 (2) ◽  
pp. 83-91 ◽  
Author(s):  
François Coutlee ◽  
Danielle Rouleau ◽  
Alex Ferenczy ◽  
Eduardo Franco
Keyword(s):  
Cervical Cancer ◽  
High Risk ◽  
Hpv Infection ◽  
Human Papillomaviruses ◽  
High Grade ◽  
Hpv Testing ◽  
Screening Programs ◽  
Detection Techniques ◽  
Hpv Types ◽  
High Risk Hpv

Human papillomaviruses (HPVs) are the etiological agents of several genital cancers, including cancer of the uterine cervix. The detection of HPV infection in genital samples may increase the sensitivity of primary and secondary screenings of cervical cancer. HPV testing may also improve the specificity of screening programs, resulting in the avoidance of overtreatment and cost savings for confirmatory procedures. The major determinants of clinical progression of HPV infection include persistence of HPV infection, involvement of high-risk HPV types, high HPV viral load, integration of viral DNA and presence of several potential cofactors. Signal amplification HPV-DNA detection techniques (Hybrid Capture II, Digene Corporation, USA) are standardized, commercially available, and capable of detecting several high-risk HPV types. They also increase the sensitivity of screening for high-grade lesions in combination with cytology. The sensitivity of these techniques to detect high-grade lesions is higher than that of cytology, but the referral rate for colposcopy is greater. These techniques are approved for the triage to colposcopy of women with cervical smears interpreted as atypical squamous cells of undetermined significance. Triage and screening for cervical cancer using HPV will probably be restricted to women aged 30 years or older because of the high prevalence of infection in younger women. Amplification techniques are ideal for epidemiological studies because they minimize the misclassification of HPV infection status. These techniques can detect low HPV burden infections. Consensus primers amplify most genital types in one reaction, and the reverse hybridization of amplicons with type-specific probes allows for the typing of HPV-positive samples. Consensus PCR assays are currently under evaluation for diagnostic purposes. HPV testing is currently implemented for the clinical management of women.

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