Human Papillomavirus Type 33 Polymorphisms and High‐Grade Squamous Intraepithelial Lesions of the Uterine Cervix

Khouadri, Soraya; Villa, Luisa L.; Gagnon, Simon; Koushik, Anita; Richardson, Harriet; Ferreira, Silvaneide; Tellier, Pierre; Simao, João; Matlashewski, Greg; Roger, Michel; Franco, Eduardo L.; Coutlée, François

doi:10.1086/507431

Cited by 33 publications

(52 citation statements)

References 43 publications

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“…HPV16 and -33 are high-risk HPVs frequently detected in cervical cancer. Naturally occurring variants of HPV16 and -33 with polymorphisms in the E6 open reading frame (ORF) have been reported (18,22,32,58,72), some of which have been linked to oncogenicity (23,47,73). To investigate whether these polymorphisms have an impact on p53 degradation by E6, we performed p53 expression assays in the presence of HPV16 E6 variants R10G, L83V, and R10G/L83V, as well as HPV33 E6 K35N (N), K35N/N86H (NH), I73L/V83L/K93N/ A138V (LLNV), P36T/I73L/V83L/K93N/A138V (TLLNV), and A18V/P36T/I73L/V83L/K93N/A138V (VTLLNV) and the prototype HPV16 E6 and HPV33 E6 (Fig.…”

Section: Resultsmentioning

confidence: 99%

p53 Degradation Activity, Expression, and Subcellular Localization of E6 Proteins from 29 Human Papillomavirus Genotypes

Mésplède

Gagnon

Bergeron-Labrecque

et al. 2012

J Virol

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Human papillomaviruses (HPVs) are the etiological agents of cervical cancer and other human malignancies. HPVs are classified into high-and low-risk genotypes according to their association with cancer. Host cell transformation by high-risk HPVs relies in part on the ability of the viral E6 protein to induce the degradation of p53. We report the development of a cellular assay that accurately quantifies the p53 degradation activity of E6 in vivo, based on the fusion of p53 to Renilla luciferase (RLuc-p53). This assay was used to measure the p53 degradation activities of E6 proteins from 29 prevalent HPV types and variants of HPV type 16 (HPV16) and HPV33 by determining the amount of E6 expression vector required to reduce by half the levels of RLuc-p53 (50% effective concentration [EC 50 ]). These studies revealed an unexpected variability in the p53 degradation activities of different E6 proteins, even among active types whose EC 50 s span more than 2 log units. Differences in activity were greater between types than between variants and did not correlate with differences in the intracellular localization of E6, with most being predominantly nuclear. Protein and mRNA expression of the 29 E6 proteins was also examined. For 16 high-risk types, spliced transcripts that encode shorter E6*I proteins of variable sizes and abundances were detected. Mutation of the splice donor site in five different E6 proteins increased their p53 degradation activity, suggesting that mRNA splicing can limit the activity of some highrisk E6 types. The quantification of p53 degradation in vivo represents a novel tool to systematically compare the oncogenic potentials of E6 proteins from different HPV types and variants.

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Section: Resultsmentioning

confidence: 99%

p53 Degradation Activity, Expression, and Subcellular Localization of E6 Proteins from 29 Human Papillomavirus Genotypes

Mésplède

Gagnon

Bergeron-Labrecque

et al. 2012

J Virol

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“…An even higher disconcordance rate was detected by pyrosequencing of HPV-16 variants in a recent study of human immunodeficiency virus-infected adults [14]. Other studies have reported identical variants in consecutive samples positive for HPV-16 [11,12] or other high-risk types [15]. Although the inconsistent results can in part be explained by differences in study populations, interval durations, and approaches for variant characterization, most of these studies were limited by small sample size.…”

Section: Prospective Studies Of the Persistence Of Human Papillomavirmentioning

confidence: 98%

Human Papillomavirus Type 16 Variants in Paired Enrollment and Follow‐up Cervical Samples: Implications for a Proper Understanding of Type‐Specific Persistent Infections

Koutsky

Castle

et al. 2010

J INFECT DIS

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Prospective studies of the persistence of human papillomavirus (HPV) variants are rare and typically small. We sequenced HPV-16 variants in longitudinal pairs of specimens from 86 women enrolled in the ASCUS-LSIL Triage Study.A change of variants was identified in 4 women (4.7% [95% confidence interval, 1.3%-11.5%]). Among women with intervening HPV results ( ), a variant switch occurred n p 60 in 2 of 11 who had evidence of intervening negativity for HPV-16, compared with 1 of 49 who consistently tested positive ( ). These results suggest the possibility that rare P p .11 misclassification of transient infections as persistent infections occurs in natural history studies of type-specific HPV infections.Studies of the natural history of human papillomavirus (HPV) infection define viral persistence at a type-specific level-that is, as the same genotype of HPV DNA detected during a certain time period. Intervening negativity is usually assumed to be the result of fluctuation in viral DNA load to below a detectable threshold [1]. In practice, it is difficult to distinguish typespecific persistence from recurrent infection.In light of the intratypic diversity of the HPV genome [2], the persistence of type-specific HPV infection may be better defined by analyses of nucleotide alterations in viral isolates [3]. For any given type of HPV, isolates that differ by !2% in the DNA sequence of the L1 (conserved major capsid) gene are designated as variants. Because HPV evolution is slow (genetic drift occurs at approximately the same rate as in the human genome) [4], spontaneous mutations in HPV variants during the life span of infected hosts occur extremely rarely. Accordingly, different variants in consecutive samples from an individual most likely represent separate infections.In the present study, we compared sequence variations in HPV-16 variants in pairs of specimens collected prospectively from a subset of women who were enrolled in a nested casecontrol study investigating the clinical relevance of HPV-16 variants.Methods. Cervical samples examined were from the casecontrol study of women enrolled in the ASCUS-LSIL Triage Study (ALTS), a randomized, multicenter, clinical trial designed to evaluate strategies for the management of equivocal and mildly abnormal cervical cytology. These women were followed semiannually over 2 years for HPV typing and detection of cervical lesions. A detailed description of the ALTS design and study population has been presented elsewhere [5].Case patients were women who had (1) cervical intraepithelial neoplasia grade 2 or 3 (CIN2-3) initially diagnosed during follow-up and (2) HPV-16 DNA detected by polymerase chain reaction (PCR)-based reverse line blot [6] at follow-up visits concurrent with or before the diagnosis of CIN2-3. Control patients were selected from those who did not have a diagnosis of CIN2-3 during the entire study period and had HPV-16 DNA detected at 1 or more follow-up visits. The study protocol was approved by the institutional human subject review board of the Unive...

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“…The non-E HPV 18 variants are more frequently identified in cancer tissues and high-grade lesions (23)(24)(25) . HPV 33 (C7732G) and HPV 58 (C632T and G760A) variants were associated with a higher risk for cervical cancer (26,27) than that observed for infectios with "prototypes" of the same HPV 33 and 58.…”

Section: Introductionmentioning

confidence: 85%

Low and High-Oncogenic Risk Human Papillomaviruses: Every Rule Has its Exception

Oliveira¹

2011

J bras doenças sex transm

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Human Papillomavirus Type 33 Polymorphisms and High‐Grade Squamous Intraepithelial Lesions of the Uterine Cervix

Abstract: Intratypic LCR variants of HPV-33 seem to vary geographically and to differ with respect to their oncogenic potential.

Cited by 33 publications

References 43 publications

p53 Degradation Activity, Expression, and Subcellular Localization of E6 Proteins from 29 Human Papillomavirus Genotypes

p53 Degradation Activity, Expression, and Subcellular Localization of E6 Proteins from 29 Human Papillomavirus Genotypes

Human Papillomavirus Type 16 Variants in Paired Enrollment and Follow‐up Cervical Samples: Implications for a Proper Understanding of Type‐Specific Persistent Infections

Low and High-Oncogenic Risk Human Papillomaviruses: Every Rule Has its Exception

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