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The evolution of the major hepatitis C genotypes correlates with clinical response to interferon therapy.

Pang PS, Planet PJ, Glenn JS - PLoS ONE (2009)

Bottom Line: This resulted in a new cladogram of HCV.This tree establishes for the first time the relative evolutionary ages of the major HCV genotypes.An evolutionary analysis of all available HCV genomes supports the hypothesis that immune selection was a significant driving force in the divergence of the major HCV genotypes and that viral factors that acquired the ability to inhibit the immune response may play a role in determining genotype-specific response rates to interferon therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Infectious Diseases and Geographic Medicine and Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, CA, USA.

ABSTRACT

Background: Patients chronically infected with hepatitis C virus (HCV) require significantly different durations of therapy and achieve substantially different sustained virologic response rates to interferon-based therapies, depending on the HCV genotype with which they are infected. There currently exists no systematic framework that explains these genotype-specific response rates. Since humans are the only known natural hosts for HCV-a virus that is at least hundreds of years old-one possibility is that over the time frame of this relationship, HCV accumulated adaptive mutations that confer increasing resistance to the human immune system. Given that interferon therapy functions by triggering an immune response, we hypothesized that clinical response rates are a reflection of viral evolutionary adaptations to the immune system.

Methods and findings: We have performed the first phylogenetic analysis to include all available full-length HCV genomic sequences (n = 345). This resulted in a new cladogram of HCV. This tree establishes for the first time the relative evolutionary ages of the major HCV genotypes. The outcome data from prospective clinical trials that studied interferon and ribavirin therapy was then mapped onto this new tree. This mapping revealed a correlation between genotype-specific responses to therapy and respective genotype age. This correlation allows us to predict that genotypes 5 and 6, for which there currently are no published prospective trials, will likely have intermediate response rates, similar to genotype 3. Ancestral protein sequence reconstruction was also performed, which identified the HCV proteins E2 and NS5A as potential determinants of genotype-specific clinical outcome. Biochemical studies have independently identified these same two proteins as having genotype-specific abilities to inhibit the innate immune factor double-stranded RNA-dependent protein kinase (PKR).

Conclusion: An evolutionary analysis of all available HCV genomes supports the hypothesis that immune selection was a significant driving force in the divergence of the major HCV genotypes and that viral factors that acquired the ability to inhibit the immune response may play a role in determining genotype-specific response rates to interferon therapy.

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Related in: MedlinePlus

Unrooted HCV Cladograms From Previous Studies.Panel A shows the first cladogram to divide HCV into six genotypes, based on a neighbor-joining analysis of the NS5 region of HCV that included 76 sequences (Simmonds et al. 1993). Panel B shows a more recent HCV consensus tree with a different genotype branching pattern compared to Panel A, based on an analysis of 27 full-length HCV genomic sequences (Salemi et al. 2002). The table below each panel indicates the genotype distribution of the sequences analyzed in these studies.
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pone-0006579-g001: Unrooted HCV Cladograms From Previous Studies.Panel A shows the first cladogram to divide HCV into six genotypes, based on a neighbor-joining analysis of the NS5 region of HCV that included 76 sequences (Simmonds et al. 1993). Panel B shows a more recent HCV consensus tree with a different genotype branching pattern compared to Panel A, based on an analysis of 27 full-length HCV genomic sequences (Salemi et al. 2002). The table below each panel indicates the genotype distribution of the sequences analyzed in these studies.

Mentions: HCV was first divided into genotypes by the seminal work of Simmonds and others in 1993 [20], [21], based on an analysis of one segment of the HCV genome from 76 different patients (Figure 1A). Evolutionary analysis limited to only portions of a genome, however, can be misleading [18], [21], [22]. For instance, by analyzing 27 full-length HCV genomes Salemi and colleagues [23] (Figure 1B) found a different phylogenetic pattern for the relationships amongst the six HCV genotypes. Also of note is that neither analysis determined the relative evolutionary ages of the various genotypes.


The evolution of the major hepatitis C genotypes correlates with clinical response to interferon therapy.

Pang PS, Planet PJ, Glenn JS - PLoS ONE (2009)

Unrooted HCV Cladograms From Previous Studies.Panel A shows the first cladogram to divide HCV into six genotypes, based on a neighbor-joining analysis of the NS5 region of HCV that included 76 sequences (Simmonds et al. 1993). Panel B shows a more recent HCV consensus tree with a different genotype branching pattern compared to Panel A, based on an analysis of 27 full-length HCV genomic sequences (Salemi et al. 2002). The table below each panel indicates the genotype distribution of the sequences analyzed in these studies.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2719056&req=5

pone-0006579-g001: Unrooted HCV Cladograms From Previous Studies.Panel A shows the first cladogram to divide HCV into six genotypes, based on a neighbor-joining analysis of the NS5 region of HCV that included 76 sequences (Simmonds et al. 1993). Panel B shows a more recent HCV consensus tree with a different genotype branching pattern compared to Panel A, based on an analysis of 27 full-length HCV genomic sequences (Salemi et al. 2002). The table below each panel indicates the genotype distribution of the sequences analyzed in these studies.
Mentions: HCV was first divided into genotypes by the seminal work of Simmonds and others in 1993 [20], [21], based on an analysis of one segment of the HCV genome from 76 different patients (Figure 1A). Evolutionary analysis limited to only portions of a genome, however, can be misleading [18], [21], [22]. For instance, by analyzing 27 full-length HCV genomes Salemi and colleagues [23] (Figure 1B) found a different phylogenetic pattern for the relationships amongst the six HCV genotypes. Also of note is that neither analysis determined the relative evolutionary ages of the various genotypes.

Bottom Line: This resulted in a new cladogram of HCV.This tree establishes for the first time the relative evolutionary ages of the major HCV genotypes.An evolutionary analysis of all available HCV genomes supports the hypothesis that immune selection was a significant driving force in the divergence of the major HCV genotypes and that viral factors that acquired the ability to inhibit the immune response may play a role in determining genotype-specific response rates to interferon therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Infectious Diseases and Geographic Medicine and Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, CA, USA.

ABSTRACT

Background: Patients chronically infected with hepatitis C virus (HCV) require significantly different durations of therapy and achieve substantially different sustained virologic response rates to interferon-based therapies, depending on the HCV genotype with which they are infected. There currently exists no systematic framework that explains these genotype-specific response rates. Since humans are the only known natural hosts for HCV-a virus that is at least hundreds of years old-one possibility is that over the time frame of this relationship, HCV accumulated adaptive mutations that confer increasing resistance to the human immune system. Given that interferon therapy functions by triggering an immune response, we hypothesized that clinical response rates are a reflection of viral evolutionary adaptations to the immune system.

Methods and findings: We have performed the first phylogenetic analysis to include all available full-length HCV genomic sequences (n = 345). This resulted in a new cladogram of HCV. This tree establishes for the first time the relative evolutionary ages of the major HCV genotypes. The outcome data from prospective clinical trials that studied interferon and ribavirin therapy was then mapped onto this new tree. This mapping revealed a correlation between genotype-specific responses to therapy and respective genotype age. This correlation allows us to predict that genotypes 5 and 6, for which there currently are no published prospective trials, will likely have intermediate response rates, similar to genotype 3. Ancestral protein sequence reconstruction was also performed, which identified the HCV proteins E2 and NS5A as potential determinants of genotype-specific clinical outcome. Biochemical studies have independently identified these same two proteins as having genotype-specific abilities to inhibit the innate immune factor double-stranded RNA-dependent protein kinase (PKR).

Conclusion: An evolutionary analysis of all available HCV genomes supports the hypothesis that immune selection was a significant driving force in the divergence of the major HCV genotypes and that viral factors that acquired the ability to inhibit the immune response may play a role in determining genotype-specific response rates to interferon therapy.

Show MeSH
Related in: MedlinePlus