Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and genotype assignment web resource

Abstract

The 2005 consensus proposal for the classification of hepatitis C virus (HCV) presented an agreed and uniform nomenclature for HCV variants and the criteria for their assignment into genotypes and subtypes. Since its publication, the available dataset of HCV sequences has vastly expanded through advancement in nucleotide sequencing technologies and an increasing focus on the role of HCV genetic variation in disease and treatment outcomes. The current study represents a major update to the previous consensus HCV classification, incorporating additional sequence information derived from over 1,300 (near-)complete genome sequences of HCV available on public databases in May 2013. Analysis resolved several nomenclature conflicts between genotype designations and using consensus criteria created a classification of HCV into seven confirmed genotypes and 67 subtypes. There are 21 additional complete coding region sequences of unassigned subtype. The study additionally describes the development of a Web resource hosted by the International Committee for Taxonomy of Viruses (ICTV) that maintains and regularly updates tables of reference isolates, accession numbers, and annotated alignments (http://talk.ictvonline.org/links/hcv/hcv-classification.htm). The Flaviviridae Study Group urges those who need to check or propose new genotypes or subtypes of HCV to contact the Study Group in advance of publication to avoid nomenclature conflicts appearing in the literature. While the criteria for assigning genotypes and subtypes remain unchanged from previous consensus proposals, changes are proposed in the assignment of provisional subtypes, subtype numbering beyond "w," and the nomenclature of intergenotypic recombinant.

Conclusion: This study represents an important reference point for the consensus classification of HCV variants that will be of value to researchers working in clinical and basic science fields.

Fig. 1

Phylogenetic tree of 129 representative complete coding region sequences. Up to two representatives of each confirmed genotype/subtype were aligned (together with a third extreme variant of subtypes 4g and 6e) and a neighbor joining tree constructed using maximum composite likelihood nucleotide distances between coding regions using MEGA5. Sequences were chosen to illustrate the maximum diversity within a subtype. Tips are labeled by accession number and subtype (*unassigned subtype). For genotypes 1, 2, 3, 4, and 6, the lowest common branch shared by all subtypes and supported by 100% of bootstrap replicates (n = 1,000) is indicated by ·.

Fig. 2

Distribution of p-distances between complete coding region sequences. The frequency of p-distances was calculated within and between genotypes using SSE. Intra-genotype pairwise distances were calculated for all available complete coding region sequences except for subtypes 1a, 1b, and 2b where 20 random sequences were used. For p-distances >0.15 (equivalent to a percent difference of 15%), frequencies were scaled to reduce the maximum frequency to less than 300. Distances between genotypes were calculated using one or two representatives of each confirmed and unassigned subtype, with the frequencies scaled as above.