They're like branches of the same family.
Full text of paper:
From the above:
"HCV is an enveloped virus with an RNA genome of approximately 9400 bp in length....HCV is classified in the family Flaviviridae, although it is differs in many details of its genome organization from the original (vector-borne) members of the family. HCV is additionally distinct and somewhat unusual for an RNA virus in being able to establish persistent infections in the majority of exposed individuals. This phenomenon has attracted the greatest interest in HCV research, not least because long-term, chronic infections underlie its disease manifestations and effective therapy must break this ongoing cycle of replication in the liver. Understanding the mechanism of persistence is also of fundamental immunological interest and, as discussed, represents an important new paradigm in which to explore the genetic basis for this highly adapted interaction with its host.
The evolution of HCV is shaped by distinct selection pressures that are associated with, on one hand, the historical events underlying the adaptation of HCV to its human host that have ensured its successful ongoing transmission. On the other hand, HCV is capable of very rapid, adaptive changes that are associated with de novo infection of each individual in response to immunological selection pressures to antiviral therapy. HCV also accumulates sequence changes as a result of ‘neutral’ sequence drift over time and this process, rather than the adaptive changes, accounts for much of the sequence diversity that is observed between its different genotypes.
Virus sequence change
The evolution of viruses resembles that of all organisms; it is a process that is ultimately dependent on mutations in their genetic material. In many ways, however, viruses differ from commonly studied organisms such as the geneticist's mouse or fruit fly, particularly in their speed of sequence change, large population size and the nature of the selection pressures that they encounter.
In popular use, the word ‘evolution’ describes the process of adaptive change whereby organisms change in their phenotype (such as body shape or behaviour) in response to external, sometimes changing, selection pressures and by competition with other organisms for limited resources in a shared environment. Random mutations from copying errors or chromosomal damage occasionally (and entirely by chance) might improve organism fitness, allowing the mutated gene to spread and, eventually, to predominate in the population where the advantage it confers, in terms of reproductive success, is significant. In this model, the evolution of distinct species of animals, plants and bacteria results from large numbers of incremental changes in phenotype that are associated with adaptation to the wide range of separate contemporary and previous environments.
Surprisingly, this ‘Darwinian’ type of evolution makes very little contribution to the genetic diversity of organisms when measured at the level of DNA or RNA sequences. Although highly controversial when proposed (Kimura, 1968; King & Jukes, 1969), neutral theory demonstrates that the majority of sequence change in and between species has no significant effect on phenotype, i.e. it is ‘neutral’ (Kimura, 1983). Nucleotide changes in coding and non-coding sequences that have little or no effect on organism fitness become fixed in the population by chance. Thus, geographically isolated members of species can become very different genetically, whilst often remaining unchanged morphologically and behaviourally. The frequency of fixation of neutral changes can be predicted to be relatively constant over time and underlies the remarkably close correlation between sequence divergence of certain genes, such as haemoglobin, with the established chronology of splitting of different mammalian species and orders over the past 150 million years..."
"Evidence for both ‘Darwinian’ and neutral evolution can be found in the sequences of HCV. One possible example of adaptive change in HCV is the rapid evolution of the hypervariable region of the E2 envelope glycoproteins to prevent recognition by antibodies that are induced by infection (see the section entitled ‘Sequence variability within genotypes’). In contrast, ‘neutral’ sequence drift undoubtedly accounts for much of the genetic diversity that is observed between geographically or epidemiologically separated populations of HCV. This process of divergence resulting from the fixation of neutral sequence changes does not alter the phenotype of the viruses greatly. Despite the >30 % sequence difference that is observed between genotypes of HCV (see the section entitled ‘HCV genotypes’), each retains a similar replication cycle in human hosts. Indeed, their shared abilities to establish persistent infections in humans with high infectivity titres in blood and to cause only slowly progressive and largely asymptomatic infection are key factors in their ongoing transmission. This lack of phenotypic innovation over an extremely long period of divergent evolution demonstrates, perhaps, how the evolution of HCV is shaped and constrained entirely by its close adaptation to the particular ecological niche it inhabits, the human liver.
HCV genetic diversity and genotypes
Genetic variability of HCV exists at several different levels. Most obvious is the substantial genetic divergence of the main genotypes of HCV, which frequently show specific geographical ranges in the human population and associations with particular risk groups for infection. Below this and arising from sequence drift over a much shorter period is the variability that is observed between individual variants (or strains). Much of the sequence diversity that is observed between such strains (such as the 5–8 % divergence observed between variants in epidemiologically unlinked infections by HCV genotypes 1a, 1b and 3a) reflects processes of neutral sequence drift over time after the introduction of HCV into new risk groups in the 20th century. Some of the sequence divergence may represent phenotypically selected changes that are associated with adaptation for replication in individuals with different immune responses to infection (see the section entitled ‘Sequence variability within genotypes’). Finally, HCV diversifies measurably within an infected individual over time, forming what has been described as a ‘quasispecies’. This pre-existing genetic variability, combined with an extremely large replicating population size of HCV in a chronically infected individual, provides a large pool of genetic variants that can adapt to new selection pressures, such as immunological recognition and antiviral treatment.
Comparison of nucleotide sequences of variants recovered from infected individuals in different risk groups for infection and from different geographical regions has revealed the existence of at least six major genetic groups. On average over the complete genome, these differ in 30–35 % of nucleotide sites, with more variability concentrated in regions such as the E1 and E2 glycoproteins, whereas sequences of the core gene and some of the non-structural protein genes, such as NS3, are more conserved (Fig. 1). The lowest sequence variability between genotypes is found in the 5' UTR, where specific sequences and RNA secondary structures are required for replication and translation functions.
Despite the sequence diversity of HCV, all genotypes share an identical complement of collinear genes of similar or identical size. However, contrasting with this general observation is the marked variation in their capability to express a further protein that is generated by a translational frameshift at codon 11 of the core gene (Walewski et al., 2001; Xu et al., 2001; Varaklioti et al., 2002); both the frameshift site and potential size of this novel coding sequence are very poorly conserved between and within genotypes. This contrast with the evolutionarily conserved nature of so many other aspects of HCV replication supports the idea that this ‘gene’ is more likely to be a computational artefact that has arisen from RNA structure-imposed constraints on third-codon position variability in the core gene (Tuplin et al., 2004).
Each of the six major genetic groups of HCV contains a series of more closely related subtypes that typically differ from each other by 20–25 % in nucleotide sequences, compared with the >30 % divergence between genotypes (Fig. 1; Simmonds et al., 1993). Some, such as genotypes 1a, 1b and 3a, have become distributed very widely as a result of transmission through blood transfusion and needle-sharing between infecting drug users (IDUs) over the past 30–70 years and now represent the vast majority of infections in Western countries (Fig. 2). These are the genotypes that are encountered most commonly in the clinical setting and for which most information has been collected on response to interferon (IFN) and other antiviral treatments."
Excellent lecture, appreciated.
I am 1A-B (altogether), I could not find a break down of which types of gen are most difficult than the other.
Anyone have that knowledge?
The processes of neutral and adaptive evolution of HCV operate during the course of chronic infection within an individual, leading to both continued fixation of nucleotide changes over time and the development of variable degrees of sequence diversity within the replicating population at a given time point. Sequence diversity is generated continually during virus replication, as RNA copying by the virally encoded RNA polymerase (NS5B) is error-prone and the replicating population is so large. For example, ongoing error rates of between 1 in 10 000 and 1 in 100 000 bp copied, which are typically found for RNA polymerases (reviewed by Domingo et al., 1996; Drake et al., 1998), combined with a rate of virus production of up to 1012 virions per day (Neumann et al., 1998), would produce a highly genetically diverse population of variants, containing mutants that differed at every nucleotide position and every combination of paired differences from the population mean or consensus.
Even though the consensus sequence may be close to the fitness peak at any one time, the existence of a large and diverse population would allow rapid, adaptive (Darwinian) changes in response to changes in the replication environment. This might take the form of evolving immune responses that select against viruses with specific T- or B-cell epitopes; it might also confer resistance to antiviral agents. The rapid and reproducible independent appearance of specific amino acid changes that are associated with the acquisition of HIV-1 resistance to reverse transcriptase and protease inhibitors is a dramatic demonstration of Darwinian evolution of the ‘quasispecies’. In the future, this may be reproduced in HCV infections that are treated with the new generation of protease inhibitors (such as BILN 2061) and RNA polymerase inhibitors (Lamarre et al., 2003; Pause et al., 2003; Trozzi et al., 2003; Lu et al., 2004; Sarisky, 2004).
Recombination occurs in many families of RNA viruses, its occurrence requiring both epidemiological opportunity and biological compatibility. In positive-stranded RNA viruses, recombination generally occurs through a process of template-switching during RNA genomic replication. To detect such occurrences, a single cell must be infected with two or more genetically identifiable variants of the virus. In vivo, this requires both coinfection of the same individual with more than one such variant and substantial overlap in their geographical distributions, in order to enable recombinant forms to be detected.
The genotype epidemiology and natural history of infection with HCV clearly fulfils both of these criteria. A wide range of genotypes circulates in the main risk groups for HCV in Western countries, including 1a and 3a in IDUs and 1b, 2a–2c and 4a throughout the Mediterranean area. In these areas, infection is often characterized by multiple exposures around the time of primary infection, such as frequently repeated needle-sharing with several infected individuals over short time-intervals in the case of IDUs and the contamination of blood products, such as factor VIII clotting factor concentrates, with multiple HCV-positive plasma units. Indeed, even ongoing, chronic HCV infection does not protect from reinfection in experimentally challenged chimpanzees (Farci et al., 1992) or in HCV-contaminated blood or blood-product recipients, such as thalassaemics and haemophiliacs (Kao et al., 1993; Jarvis et al., 1994; Lai et al., 1994)....
It is difficult to estimate the length of time that HCV has been present in human populations. As described above, the diversity of variants within genotypes 1, 2 and 4 in sub-Saharan Africa and of genotypes 3 and 6 in South-East Asia suggests that HCV may have been endemic in these populations for considerably longer than in Western countries. As the evolutionary process of sequence divergence that led to the diversity of subtypes in these regions is likely to have been predominantly neutral in mechanism, it may therefore be possible to calculate the times of splitting of subtypes and, possibly, also the times of divergence of the six main clades of HCV through use of published rates of sequence change over time (Okamoto et al., 1992; Smith et al., 1997).
Extrapolation of these rates to time the 20 and 30 % sequence divergence that is observed between subtypes and genotypes, respectively, produces relatively recent times of origin that, in many ways, are difficult to reconcile with the epidemiology of HCV and its global distribution. For example, the diversity of variants observed in west African genotype 2 sequences predicts a time of origin for this endemic pattern of infection of approximately 200–250 years ago, whilst different genotypes would have diverged from each other about 100 years earlier. Even by using complex methods for correction for multiple substitutions and allowing rate variation between sites, the current diversity of genotypes predicts an origin no earlier than 1000 years ago (Smith et al., 1997). This seems to be too recent for such a widely distributed virus that infects often relatively isolated human populations in equatorial Africa and South-East Asia. "
From Richard Sallie's "Replicative Homeostasis III'
7.0 Replicative Homeostasis
"The mechanism of RH has been described in detail previously  but, in brief, it is proposed to result from differential interactions of wild-type (wt) and variant (mt) envelope and envelope related proteins on RNApol in a series of feedback epicycles that link RNApol functions fidelity and processivity, RNA replication and viral protein synthesis, structure and function (Figures (Figures2,2, ,3),3), such that, in general terms, excess production of mutant envelope proteins, reflecting inadequate replicative fidelity, interact with RNApol to increase its fidelity and reduce processivity, while excess production of wild type (consensus sequence) envelope sequences, reflecting overly faithful replication (rendering the virus susceptible to immune-mediated clearance or destruction through attenuation and loss of replicative plasticity), interact with RNApol causing decreased fidelity. The ineluctable consequence of these interactions is the formation of highly stable, but reactive equilibria that permit viruses to respond rapidly to adverse changes to their conditions (e.g. immune recognition of dominant epitopes) and changing characteristics (e.g. evolving receptor polymorphisms) of their hosts.
Several independent lines of evidence strongly suggest that RH is mediated in HCV by interactions between the E2 protein, with probable contribution from P7 that likely 'fine-tunes' RNApol modulation in a manner similar to that proposed for HIVnef , and the interferon sensitivity region (ISDR) of NS5A and the thumb domain of the RNA-dependent RNA polymerase from NS5B. First, these regions are obviously important for genotype-specific virus related functions; HCV genotypes characteristically vary in length, with genotype 1 typically comprising 9030 to 9042 nucleotides, genotype 2 has 9099 and genotype 3 9063 nucleotides. The nucleotide insertions or deletions responsible for these genotype-specific differences are found within the E2 and NS5 portions of the genome"
WOW!!!!! thank you so much!!!!