HCV Genotypes

The first complete HCV genome sequence was reported by Choo et al. in 1991.24 As additional genome sequences from isolates from different parts of the world were determined and compared, it was evident that HCV exists as distinct genotypes with as much as 35% sequence diversity over the whole viral genome.25 Much of the early literature on geno-typing is confusing because investigators developed and used their own classification schemes. However, a consensus nomenclature system was developed in 1994. In this system the genotypes are numbered using Arabic numer-

Table 37-3. Terms Describing Genomic Heterogeneity of HCV

% Nucleotide

Term

Definition

Similarity*

Genotype

Heterogeneity among different

66-69

viruses

Subtype

Closely related viruses within

77-80

each genotype

Quasispecies

Complex of genetic variants

91-99

within individual viruses

Source: Adapted from Zein NN. Clinical significance of hepatitis

C virus genotypes. Clin Microbiol Rev. 2000;13:223-235.

*Full-length genome sequence identity.

als in order of their discovery, and the more closely related strains within some types are designated as subtypes with lowercase letters. The complex of genetic variants found within an individual isolate is termed the "quasispecies." The quasispecies result from the accumulation of mutations that occur during viral replication in the host. The terminology and degree of nucleotide similarity that define the relationships of HCV variants are given in Table 37-3.

Six major HCV genotypes have been identified. Sequence analysis of the E1 region suggested that HCV could be grouped into six major genotypes and 12 subtypes.26 The same investigators sequenced 573 nt of the core region of the same isolates to confirm this classification scheme.27 Simmonds et al.28 also were able to classify HCV isolates into the same six major genotypes and numerous subtypes using sequence analysis of the NS5B region. Analyses of full-length open reading frame sequences have confirmed the original classification scheme based on analyses of individual gene regions.29

Genome sequence analysis of HCV isolates from Southeast Asia have led some authors to propose new major genotypes 7, 8, 9,10, and 11.30,31 However, other investigators suggested that these variants could be classified within the six major genotypes originally described.32 Under this scheme, genotype 10 is a divergent subtype of genotype 3, and genotypes 7, 8, 9, and 11 are divergent subtypes of genotype 6.

HCV genotypes 1, 2, and 3 are found throughout the world, but there are clear differences in their distribution.33 HCV subtypes 1a, 1b, 2a, 2b, 2c, and 3a are responsible for more than 90% of infections in North and South America, Europe, and Japan. In the United States, type 1 accounts for approximately 70% of the infections with equal distribution between subtypes 1a and 1b. In Japan, subtype 1b causes more than 70% of HCV infections. Although subtypes 2a and 2b have wide distributions in North America, Europe, and Japan, subtype 2c is widespread in a region of northern Italy. HCV subtype 3a is common among intravenous drug users in the United States and Europe. Other subtypes of genotype 3 are common in Nepal, Bangladesh, India, and Pakistan.

Genotype 4 is prevalent in North Africa and the Middle East, and genotypes 5 and 6 are limited to South Africa and Hong Kong, respectively.28 Subtype 4a constitutes the majority of infections in Egypt, and this and other subtypes of genotype 4 are found in Zaire and Gabon. Subtype 5a is a particular problem in South Africa, where some reports indicate that it is responsible for more than 50% of infections. Subtype 6a infections are common in Hong Kong. The isolates classified as genotypes 7, 8, and 9 by some investigators have been found only in Vietnamese patients.31 Putative genotypes 10 and 11 have been identified only in patients from Indonesia.30

The retrospective nature of most of the studies makes it difficult to determine the role of genotype as a risk factor for disease progression and to separate it from other known risk factors, such as older age at infection, male gender, alcohol consumption, and concurrent viral infection. However, in two prospective studies, viral genotype did not correlate with disease progression.34,35

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