The natural history of human papillomavirus infections of the mucosal epithelia

Chow, Louise T.; Broker, Thomas R.; Steinberg, Bettie M.

doi:10.1111/j.1600-0463.2010.02625.x

Cited by 178 publications

(172 citation statements)

References 140 publications

(177 reference statements)

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“…Typically, viral DNA is maintained as low copy nuclear plasmids in basal and parabasal keratinocytes, and vegetative amplification depends on squamous differentiation (review in ref. 3). Because viral DNA replication requires the host DNA replication machinery, the role of the HPV E7 protein is to promote S-phase reentry in differentiated cells that have withdrawn from the cell cycle.…”

mentioning

confidence: 99%

HPV-18 E6 mutants reveal p53 modulation of viral DNA amplification in organotypic cultures

Kho

Wang

Banerjee

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Human papillomaviruses (HPVs) amplify in differentiated strata of a squamous epithelium. The HPV E7 protein destabilizes the p130/retinoblastoma susceptibility protein family of tumor suppressors and reactivates S-phase reentry, thereby facilitating viral DNA amplification. The high-risk HPV E6 protein destabilizes the p53 tumor suppressor and many other host proteins. However, the critical E6 targets relevant to viral DNA amplification have not been identified, because functionally significant E6 mutants are not stably maintained in transfected cells. Using Cre-loxP recombination, which efficiently generates HPV genomic plasmids in transfected primary human keratinocytes, we have recapitulated a highly productive infection of HPV-18 in organotypic epithelial cultures. By using this system, we now report the characterization of four HPV-18 E6 mutations. An E6 null mutant accumulated high levels of p53 and amplified very poorly. p53 siRNA or ectopic WT E6 partially restored amplification, whereas three missense E6 mutations that did not effectively destabilize p53 complemented the null mutant poorly. Unexpectedly, in cis, two of the missense mutants amplified, albeit to a lower extent than the WT and only in cells with undetectable p53. These observations and others implicate p53 and additional host proteins in regulating viral DNA amplification and also suggest an inhibitory effect of E6 overexpression. We show that high levels of viral DNA amplification are critical for late protein expression and report several previously undescribed viral RNAs, including bicistronic transcripts predicted to encode E5 and L2 or an alternative form of E1^E4 and L1.human papillomavirus DNA amplification | trans complementation | HPV transcripts P apillomaviruses are small DNA viruses with a protein capsid harboring a double-stranded circular genome of ∼7,900 bp. Dozens of human papillomavirus (HPV) types are tropic for the anogenital tract (1). HPV-16 and -18 and closely related genotypes are high-risk (HR) types and at a low frequency, can cause cancers, in which the viral E6 and E7 oncogenes are invariably overexpressed. HPV-6 and -11 are low-risk (LR) types and induce benign anogenital warts and laryngeal papillomas (review in ref. 2). Typically, viral DNA is maintained as low copy nuclear plasmids in basal and parabasal keratinocytes, and vegetative amplification depends on squamous differentiation (review in ref.3). Because viral DNA replication requires the host DNA replication machinery, the role of the HPV E7 protein is to promote S-phase reentry in differentiated cells that have withdrawn from the cell cycle. It does so by destabilizing the p130 protein (4, 5), a pocket protein related to the retinoblastoma susceptibility protein, a major tumor suppressor. The HR but not the LR HPV E7 protein also destabilizes retinoblastoma susceptibility protein (6). Both HR and LR HPV E6 proteins inactivate the transcription regulatory activities of another major tumor suppressor, p53 (7-10), abrogating its control over cell cycle ar...

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confidence: 99%

HPV-18 E6 mutants reveal p53 modulation of viral DNA amplification in organotypic cultures

Kho

Wang

Banerjee

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Human papillomaviruses (HPV) 2 are small double-stranded DNA tumor viruses of considerable medical importance. They infect epithelial tissues, causing benign hyperproliferative lesions.…”

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confidence: 99%

Human Papillomavirus (HPV) E7 Induces Prolonged G2 following S Phase Reentry in Differentiated Human Keratinocytes

Banerjee

Wang

Broker

et al. 2011

Journal of Biological Chemistry

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101

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Human papillomaviruses (HPV)2 are small double-stranded DNA tumor viruses of considerable medical importance. They infect epithelial tissues, causing benign hyperproliferative lesions. More than 120 HPV genotypes have been cloned from patient specimens. The mucosotropic HPVs are broadly grouped into high-risk (HR) or low-risk (LR) types (1). Persistent infections of the cervix, penis, anus, and the oropharyngeal epithelium by HR HPV-16, HPV-18, and related types can at a low frequency progress into high grade dysplasias and cancers. Infections by LR HPV types 6 and 11 cause 90% of benign genital warts and all the laryngeal papillomas, and these infections rarely progress to cancers. For both HR and LR HPVs, infection initiates in basal epithelial keratinocytes through wounding and is established during healing, whereas the viral productive program is tightly linked to squamous differentiation (for a review, see Ref.2). Because the differentiated spinous cells would normally have withdrawn from the cell cycle and viral DNA replication is dependent on the host DNA replication machinery, the roles of the viral E6 and E7 oncoproteins are to reestablish a milieu in the differentiated keratinocytes supportive for viral DNA amplification. Briefly, E7 proteins of HR and LR HPV types promote S phase reentry in the differentiated strata (3, 4). They do so by destabilizing p130, a pRB related pocket protein, which prevents S phase reentry by the differentiated cells (5, 6). The mechanisms by which E6 enables efficient viral DNA amplification are not yet understood.The viral life cycle has recently been recapitulated with high efficiency in organotypic (raft) cultures of primary human keratinocytes (PHKs) grown at the liquid medium-air interface. In these PHKs, HPV-18 genomic plasmids were efficiently generated in vivo by Cre-loxP-mediated excision recombination from a transfer vector (7). As in patient specimens, the doublestranded HPV genomic plasmid is maintained at low copy numbers in the basal keratinocytes, and extensive amplification occurs in the mid and upper spinous strata. Moreover, viral DNA initiates amplification in G 2 -arrested cells, following host DNA replication, as revealed by the accumulation of highly elevated cytoplasmic cyclin B1 protein (7). As the viral DNA amplifies, the E7 activity progressively diminishes and eventually ceases in the upper strata; keratinocytes then exit the cell cycle, as evidenced by the gradual reappearance of p130 and disappearance of the proliferating cell nuclear antigen, a protein induced by E7. Being an E2F-responsive gene, cyclin B1 disappears when E7 activity ceases. These cells then transit to the late phase of infection and express the capsid proteins for progeny virion morphogenesis. Here, we show that E7 alone is necessary and sufficient to induce prolonged G 2 following S phase reentry in differentiated keratinocytes of raft cultures and have investigated the mechanisms that mediate this arrest.

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“…The low-risk types such as hpv-6 and hpv-11 (10 species) cause stigmata of the epithelia frequently labelled "warts," "condylomata," or "papillomas"-each name being derived from the associated site of infection (for example, "anogenital warts" and so on). Among the high-risk types, hpv-16 (9 species), hpv-18 (7 species), hpv-51 (5 species), and hpv-53 (6 species) are oncogenic and induce lesions of varying degrees of dysplasia, many of which progress to frank neoplasias such as tonsillar, oropharyngeal, penile, vaginal, anal, or cervical cancers, or to other oral and head-and-neck cancers 2 . The hpvs also induce oral lesions such as focal epithelial hyperplasia (previously known as Heck disease 3,4 ) and may cause ocular papillomas on the conjunctivae 5 .…”

Section: Background and Provenancementioning

confidence: 99%

The Kiss of Death: HPV Rejected by Religion

Touyz

2013

Current Oncology

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Although hpv infections are transmitted mainly through sexual intercourse, they are also frequently transmitted non-sexually; consequently adults and children alike are often infected 6 . Non-sexual forms of transmission include various forms of kissing, vertical transmission from mother to child at birth, social physical contacts, and latency in the respiratory tract 7,8 .The prevalences of alcohol-and tobacco-derived cancers are waning, but head-and-neck cancers from hpv are increasing 9 .

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The natural history of human papillomavirus infections of the mucosal epithelia

Cited by 178 publications

References 140 publications

HPV-18 E6 mutants reveal p53 modulation of viral DNA amplification in organotypic cultures

HPV-18 E6 mutants reveal p53 modulation of viral DNA amplification in organotypic cultures

Human Papillomavirus (HPV) E7 Induces Prolonged G2 following S Phase Reentry in Differentiated Human Keratinocytes

The Kiss of Death: HPV Rejected by Religion

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