Genetic heterogenicity of HCV seems to play a role in the evolutionary course of hepatitis C infection. The spread and origins of HCV in human populations have been the subject of extensive investigations, not only because this information would provide explanation of the long asymptomatic stage of HCV infection and its slow disease progression but also it helps in predicting clinical outcomes and controlling spread of HCV in the future. This is vital for health planning and management of currently asymptomatic individuals.
For many RNA viruses, relatively rapid generations of virus variants are implied by the high rate of nucleotide substitution observed in longitudinal studies. Ina et al., (1994) concluded that the rate of HCV sequence change in core region was 1.5-2 x 10 –3 per site per year. On other hand, Smith et al., (1997) measured this in the E1 and NS5B genes and the estimated rates were 4•1 and 7•1x10-4 per site per year respectively.
Types of heterogenicity
HCV is genetically heterogeneous and is characterized by the existence of quasispecies distribution of the virus population within a single infected individual and the different genotypes with more closely related subtypes all over the world (Szabo et al., 2003).
Sequence analysis of a large number of cDNA clones of HCV from single isolate has provided evidence that the HCV genome cannot be defined by a single sequence, but rather by a population of variant sequences closely related to one another but yet of heterogeneous genomes. This manner of organizing the genetic information is called quasispecies (Gomez et al., 1999 and Abid et al., 2000).
It results from accumulation of mutations that either present from the onset of infection due to simultaneous transmission of multiple viral species or result during viral replication in the host. This occurs because HCV replicates at high levels while employing its error-prone RdRp that lacks the repair mechanisms as 3’- 5’ exonuclease proofreading activity important for removal of misincorporated bases during DNA replication (Forns and Bukh, 1999).
Ray et al., (2000) and Liu et al., (2004) reported another explanation is that the sequence variation results from an interaction between the host and the virus. The immune response of the infected individuals performs various selective pressures on the HCV with its great ability to accommodate which drives some sort of sequence variation.
Piron et al., (2005) informed that, part of the variability present in the RNA sequences of the viral population may be represented in secondary or tertiary RNA structures, providing alternative conformations. This variability could potentially modify the strength of RNA conformational signals, which represent potential substrates for selection events, or provide the signals with different meanings.
However, the variants in HCV quasispecies generally have 94-99% nucleotide identity but continuation of host selection and adaptation of a rapidly mutating genome has led to the evolution of many distinct HCV genotypes and subtypes that can be distinguished according to the actual degree of nucleotide and amino acid relatedness (Pawlotsky, 2003).
Soon after the first full HCV genome (HCV prototype or HCV-1) was determined by Choo et al., (1989) from a chimpanzee, several HCV isolates from different parts of the world were isolated and sequenced. According to a consensus nomenclature system proposed by Simmonds et al., (1994), HCV is classified on the basis of the similarity of nucleotide sequence into major genetic groups designated genotypes that are numbered (Arabic numerals) in the order of their discovery. The more closely related HCV strains within some types are designated subtypes, which are assigned lowercase letters (in alphabetic order) in the order of their discovery (Table I) (Szabo et al., 2003).
Table (I): Terminology relating to HCV genomic heterogencity (Szabo et al., 2003)
Terminology Definition % Nucleotide similarity a
Genotype (1-6) Major genetic group based on similarity of nucleotide sequence 65.7-68.9
Subtype (a, b, etc.) Genetically closely related viruses within of nucleotide sequence 76.9-80.1
Quasispecies Complex of genetic variants within individual isolates 90.8-99
a % Nucleotide similarity refers to the nucleotide sequence identities of the full-length sequences of the HCV genome
Using the phylogenetic analysis, 6 major genotypes and more than 90 subtypes has been identified. Each genotype is equally divergent from the others, by about 31 to 34% of nucleotide positions on pair wise comparison of complete genomic sequences, and leading to approximately 30% amino acid sequence divergence between the encoded polyproteins (WHO, 1999 and Podzorski, 2002).
The sequence heterogenecity between subtypes of the same genotype is approximately 21% (range, 20%–23%) (Simmonds et al., 2005).
• Clinical relevance of genotypes;
The identification and characterization of HCV genotypes and subtypes have major implications for HCV pathogenesis. In addition, the genotypes are important epidemiological markers and may alter the sensitivity and specificity of diagnostic assays. It is thought that genetic heterogenicity may account for some of the differences in disease outcome and response to treatment observed in infected persons. Moreover, genotyping may be a useful tool for tracing the source of an HCV outbreak in a given population (Martial et al., 2004).
Genetic heterogenicity of HCV seems to play a role in the evolutionary course of hepatitis C infection. The spread and origins of HCV in human populations have been the subject of extensive investigations, not only because this information would provide explanation of the long asymptomatic stage of HCV infection and its slow disease progression but also it helps in predicting clinical outcomes and controlling spread of HCV in the future. This is vital for health planning and management of currently asymptomatic individuals (Simmonds, 2004).
For many RNA viruses, relatively rapid generations of virus variants are implied by the high rate of nucleotide substitution observed in longitudinal studies. Ina et al., (1994) concluded that the rate of HCV sequence change in core region was 1.5-2 x 10 –3 per site per year. On other hand, Smith et al., (1997) measured this in the E1 and NS5B genes and the estimated rates were 4•1 and 7•1x10-4 per site per year respectively.
Types of heterogenicity
HCV is genetically heterogeneous and is characterized by the existence of quasispecies distribution of the virus population within a single infected individual and the different genotypes with more closely related subtypes all over the world (Szabo et al., 2003).
Sequence analysis of a large number of cDNA clones of HCV from single isolate has provided evidence that the HCV genome cannot be defined by a single sequence, but rather by a population of variant sequences closely related to one another but yet of heterogeneous genomes. This manner of organizing the genetic information is called quasispecies (Gomez et al., 1999 and Abid et al., 2000).
It results from accumulation of mutations that either present from the onset of infection due to simultaneous transmission of multiple viral species or result during viral replication in the host. This occurs because HCV replicates at high levels while employing its error-prone RdRp that lacks the repair mechanisms as 3’- 5’ exonuclease proofreading activity important for removal of misincorporated bases during DNA replication (Forns and Bukh, 1999).
Ray et al., (2000) and Liu et al., (2004) reported another explanation is that the sequence variation results from an interaction between the host and the virus. The immune response of the infected individuals performs various selective pressures on the HCV with its great ability to accommodate which drives some sort of sequence variation.
Piron et al., (2005) informed that, part of the variability present in the RNA sequences of the viral population may be represented in secondary or tertiary RNA structures, providing alternative conformations. This variability could potentially modify the strength of RNA conformational signals, which represent potential substrates for selection events, or provide the signals with different meanings.
However, the variants in HCV quasispecies generally have 94-99% nucleotide identity but continuation of host selection and adaptation of a rapidly mutating genome has led to the evolution of many distinct HCV genotypes and subtypes that can be distinguished according to the actual degree of nucleotide and amino acid relatedness (Pawlotsky, 2003).
Soon after the first full HCV genome (HCV prototype or HCV-1) was determined by Choo et al., (1989) from a chimpanzee, several HCV isolates from different parts of the world were isolated and sequenced. According to a consensus nomenclature system proposed by Simmonds et al., (1994), HCV is classified on the basis of the similarity of nucleotide sequence into major genetic groups designated genotypes that are numbered (Arabic numerals) in the order of their discovery. The more closely related HCV strains within some types are designated subtypes, which are assigned lowercase letters (in alphabetic order) in the order of their discovery (Table I) (Szabo et al., 2003).
Table (I): Terminology relating to HCV genomic heterogencity (Szabo et al., 2003)
Terminology Definition % Nucleotide similarity a
Genotype (1-6) Major genetic group based on similarity of nucleotide sequence 65.7-68.9
Subtype (a, b, etc.) Genetically closely related viruses within of nucleotide sequence 76.9-80.1
Quasispecies Complex of genetic variants within individual isolates 90.8-99
a % Nucleotide similarity refers to the nucleotide sequence identities of the full-length sequences of the HCV genome
Using the phylogenetic analysis, 6 major genotypes and more than 90 subtypes has been identified. Each genotype is equally divergent from the others, by about 31 to 34% of nucleotide positions on pair wise comparison of complete genomic sequences, and leading to approximately 30% amino acid sequence divergence between the encoded polyproteins (WHO, 1999 and Podzorski, 2002).
The sequence heterogenecity between subtypes of the same genotype is approximately 21% (range, 20%–23%) (Simmonds et al., 2005).
• Clinical relevance of genotypes;
The identification and characterization of HCV genotypes and subtypes have major implications for HCV pathogenesis. In addition, the genotypes are important epidemiological markers and may alter the sensitivity and specificity of diagnostic assays. It is thought that genetic heterogenicity may account for some of the differences in disease outcome and response to treatment observed in infected persons. Moreover, genotyping may be a useful tool for tracing the source of an HCV outbreak in a given population (Martial et al., 2004).
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