Human Papillomavirus Type 16 Genetic Variants: Phylogeny and Classification Based on E6 and LCR

Abstract

Naturally occurring genetic variants of human papillomavirus type 16 (HPV16) are common and have previously been classified into 4 major lineages; European-Asian (EAS), including the sublineages European (EUR) and Asian (As), African 1 (AFR1), African 2 (AFR2), and North-American/Asian-American (NA/AA). We aimed to improve the classification of HPV16 variant lineages by using a large resource of HPV16-positive cervical samples collected from geographically diverse populations in studies on HPV and/or cervical cancer undertaken by the International Agency for Research on Cancer. In total, we sequenced the entire E6 genes and long control regions (LCRs) of 953 HPV16 isolates from 27 different countries worldwide. Phylogenetic analyses confirmed previously described variant lineages and subclassifications. We characterized two new sublineages within each of the lineages AFR1 and AFR2 that are robustly classified using E6 and/or the LCR. We could differentiate previously identified AA1, AA2, and NA sublineages, although they could not be distinguished by E6 alone, requiring the LCR for correct phylogenetic classification. We thus provide a classification system for HPV16 genomes based on 13 and 32 phylogenetically distinguishing positions in E6 and the LCR, respectively, that distinguish nine HPV16 variant sublineages (EUR, As, AFR1a, AFR1b, AFR2a, AFR2b, NA, AA1, and AA2). Ninety-seven percent of all 953 samples fitted this classification perfectly. Other positions were frequently polymorphic within one or more lineages but did not define phylogenetic subgroups. Such a standardized classification of HPV16 variants is important for future epidemiological and biological studies of the carcinogenic potential of HPV16 variant lineages.

Mutation Detection of E6 and LCR Genes from HPV 16 Associated with Carcinogenesis

“…Many authors have suggested that some lineages of HPV16 show greater associations with cervical neoplasms (Londesboroug et al, 1996;Bontkes et al, 1998;Zehbe et al, 1998;Villa et al, 2000;Xi et al, 2007;Schiffman et al, 2010;Smith et al, 2011;Cornet et al, 2012). This would partially explain why some HPV16 infections progress to HSIL or cancer, while others do not (Picconi et al, 2003).…”

“…E6 and E7 are the major oncoproteins and are involved in tumorigenesis. LCR has been demonstrated to be the most variable region of HPV16 and contains the early promoter and regulatory elements involved in viral DNA replication and transcription (Cornet et al, 2012). Several authors have evaluated the association of specific HPV16 mutations with viral persistence and the development of cervical intraepithelial neoplastic lesions (Londesboroug et al, 1996: Bontkes et al, 1998Villa et al, 2000;Cornet et al, 2013).…”

Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability

“…Mpileup function from SAMtools (Li et al 2009) was used to detect SNPs and small INDELs in HPV genomes. HPV variants were classified by comparison of sequences to HPV16 lineage-specific SNPs as reported by the IARC HPV Variant Study Group (Cornet et al 2012).…”

Activities of E6 Protein of Human Papillomavirus 16 Asian Variant on miR-21 Up-regulation and Expression of Human Immune Response Genes

“…(Zhang and Tang, 2012) * HPV16 has been extensively sequenced to characterize subtypes and variants in a phylogenetic framework. According to geographic location and ethnic group, HPV16 variants have been classified into 4 lineages; 1) European-Asian (EAs) including the sublineage European (E, the prototype of HPV16) and Asian (As), 2) African 1 (AFR1), 3) African 2 (AFR2) and 4) North American/ Asian-American (NA/AA) including the sublineage North American, Asian-American 1 and Asian-American 2 (Yamada et al, 1997;Cornet et al, 2012). Epidemiological studies show an association between cervical cancer and HPV16 variants and report that HPV16 E6 variants may be more oncogenic than the prototype and thus carry a higher risk for development of invasive cervical disease (Xi et al, 2007;Schiffman et al, 2010;Gheit et al, 2011;Mosmann et al, 2015).…”