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Hepatitis C virus quasispecies in chronically infected children subjected to interferon-ribavirin therapy.

Figlerowicz M, Jackowiak P, Formanowicz P, Kędziora P, Alejska M, Malinowska N, Błażewicz J, Figlerowicz M - Arch. Virol. (2010)

Bottom Line: The first type, found in non-responders, contained a small number of closely related variants.The second type, characteristic for sustained responders, was composed of a large number of distantly associated equal-rank variants.Comparison of 445 HVR1 sequences showed that a significant number of variants present in non-responding patients are closely related, suggesting that certain, still unidentified properties of the pathogen may be key factors determining the result of CHC treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases and Child Neurology, Karol Marcinkowski University of Medical Sciences, Szpitalna 27/33, 60-572 Poznań, Poland.

ABSTRACT
Accumulating evidence suggests that certain features of hepatitis C virus (HCV), especially its high genetic variability, might be responsible for the low efficiency of anti-HCV treatment. Here, we present a bioinformatic analysis of HCV-1a populations isolated from 23 children with chronic hepatitis C (CHC) subjected to interferon-ribavirin therapy. The structures of the viral quasispecies were established based on a 132-amino-acid sequence derived from E1/E2 protein, including hypervariable region 1 (HVR1). Two types of HCV populations were identified. The first type, found in non-responders, contained a small number of closely related variants. The second type, characteristic for sustained responders, was composed of a large number of distantly associated equal-rank variants. Comparison of 445 HVR1 sequences showed that a significant number of variants present in non-responding patients are closely related, suggesting that certain, still unidentified properties of the pathogen may be key factors determining the result of CHC treatment.

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Inter-quasispecies conservation of HVR1 variants isolated from non-responders. Phylogenetic analysis was carried out with selected HCV quasispecies isolated from non-responders at T0. Phylogenetic trees were constructed for HVR1 amino acid (a) and nucleotide (b) sequences. The individual sequences are named according to the following schema: HVR-patient-number-clone-number; e.g. HVR-P1-03-1-21, where ‘P1-03’ indicates the patient number, while ‘1-21’ refers to the clone number. In addition, the names are accompanied by geometrical symbols. All sequences representing the same quasispecies are marked with the same symbol. The percentage of trees in which the variants clustered together is indicated above the branches (values lower than 50% were removed). Branch lengths are proportional to the number of substitutions per site
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Fig3: Inter-quasispecies conservation of HVR1 variants isolated from non-responders. Phylogenetic analysis was carried out with selected HCV quasispecies isolated from non-responders at T0. Phylogenetic trees were constructed for HVR1 amino acid (a) and nucleotide (b) sequences. The individual sequences are named according to the following schema: HVR-patient-number-clone-number; e.g. HVR-P1-03-1-21, where ‘P1-03’ indicates the patient number, while ‘1-21’ refers to the clone number. In addition, the names are accompanied by geometrical symbols. All sequences representing the same quasispecies are marked with the same symbol. The percentage of trees in which the variants clustered together is indicated above the branches (values lower than 50% were removed). Branch lengths are proportional to the number of substitutions per site

Mentions: To evaluate the relationships between HVR1 variants present in different quasispecies at T0, an integrated phylogenetic tree was constructed. It was obtained based on all (445) variants identified in 23 HCV populations. While variants from sustained responders were noticeably dispersed, those derived from patients responding transiently and from non-responders tended to concentrate in clusters (Online Resource 8). Astonishingly, the variants isolated from ten non-responding children clustered into only seven groups. A more detailed analysis revealed that one of them, cluster 1, encompassed variants from five patients. Together with the closely related cluster 2, they constituted a pair grouping variants derived from six epidemiologically distinct viral populations (P1-01, P1-02, P1-03, P1-05, P2-05 and P2-19) (Online Resource 8; Fig. 3a). This observation suggested that HVR1 variants formed in different non-responding patients were often identical or quite similar. All of the analyses presented above were based on comparisons of amino acid sequences. To verify the results concerning inter-quasispecies conservation of HVR1, nucleotide sequences of variants grouping in clusters 1 and 2 were compared. Both phylogenetic analysis (Fig. 3b) and sequence alignment revealed population-specific differences occurring at the nucleotide level. Consequently, consensus sequences unique to each quasispecies could be generated (Fig. 4). This provided additional evidence that the similarity/identity between HVR1 variants was not caused by cross-contamination. These results suggest that the similar/identical HVR1 variants that were identified were already optimal: their appearance was strictly connected with the lack of patients’ response to the antiviral therapy. None of them were found in populations isolated from patients with transient and sustained response (Online Resource 8). These variants were present in viral populations before treatment and persisted at least through the first 2 weeks of its duration (Online Resource 3: identity of dominating variants between T0 and T2).Fig. 3


Hepatitis C virus quasispecies in chronically infected children subjected to interferon-ribavirin therapy.

Figlerowicz M, Jackowiak P, Formanowicz P, Kędziora P, Alejska M, Malinowska N, Błażewicz J, Figlerowicz M - Arch. Virol. (2010)

Inter-quasispecies conservation of HVR1 variants isolated from non-responders. Phylogenetic analysis was carried out with selected HCV quasispecies isolated from non-responders at T0. Phylogenetic trees were constructed for HVR1 amino acid (a) and nucleotide (b) sequences. The individual sequences are named according to the following schema: HVR-patient-number-clone-number; e.g. HVR-P1-03-1-21, where ‘P1-03’ indicates the patient number, while ‘1-21’ refers to the clone number. In addition, the names are accompanied by geometrical symbols. All sequences representing the same quasispecies are marked with the same symbol. The percentage of trees in which the variants clustered together is indicated above the branches (values lower than 50% were removed). Branch lengths are proportional to the number of substitutions per site
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2982956&req=5

Fig3: Inter-quasispecies conservation of HVR1 variants isolated from non-responders. Phylogenetic analysis was carried out with selected HCV quasispecies isolated from non-responders at T0. Phylogenetic trees were constructed for HVR1 amino acid (a) and nucleotide (b) sequences. The individual sequences are named according to the following schema: HVR-patient-number-clone-number; e.g. HVR-P1-03-1-21, where ‘P1-03’ indicates the patient number, while ‘1-21’ refers to the clone number. In addition, the names are accompanied by geometrical symbols. All sequences representing the same quasispecies are marked with the same symbol. The percentage of trees in which the variants clustered together is indicated above the branches (values lower than 50% were removed). Branch lengths are proportional to the number of substitutions per site
Mentions: To evaluate the relationships between HVR1 variants present in different quasispecies at T0, an integrated phylogenetic tree was constructed. It was obtained based on all (445) variants identified in 23 HCV populations. While variants from sustained responders were noticeably dispersed, those derived from patients responding transiently and from non-responders tended to concentrate in clusters (Online Resource 8). Astonishingly, the variants isolated from ten non-responding children clustered into only seven groups. A more detailed analysis revealed that one of them, cluster 1, encompassed variants from five patients. Together with the closely related cluster 2, they constituted a pair grouping variants derived from six epidemiologically distinct viral populations (P1-01, P1-02, P1-03, P1-05, P2-05 and P2-19) (Online Resource 8; Fig. 3a). This observation suggested that HVR1 variants formed in different non-responding patients were often identical or quite similar. All of the analyses presented above were based on comparisons of amino acid sequences. To verify the results concerning inter-quasispecies conservation of HVR1, nucleotide sequences of variants grouping in clusters 1 and 2 were compared. Both phylogenetic analysis (Fig. 3b) and sequence alignment revealed population-specific differences occurring at the nucleotide level. Consequently, consensus sequences unique to each quasispecies could be generated (Fig. 4). This provided additional evidence that the similarity/identity between HVR1 variants was not caused by cross-contamination. These results suggest that the similar/identical HVR1 variants that were identified were already optimal: their appearance was strictly connected with the lack of patients’ response to the antiviral therapy. None of them were found in populations isolated from patients with transient and sustained response (Online Resource 8). These variants were present in viral populations before treatment and persisted at least through the first 2 weeks of its duration (Online Resource 3: identity of dominating variants between T0 and T2).Fig. 3

Bottom Line: The first type, found in non-responders, contained a small number of closely related variants.The second type, characteristic for sustained responders, was composed of a large number of distantly associated equal-rank variants.Comparison of 445 HVR1 sequences showed that a significant number of variants present in non-responding patients are closely related, suggesting that certain, still unidentified properties of the pathogen may be key factors determining the result of CHC treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases and Child Neurology, Karol Marcinkowski University of Medical Sciences, Szpitalna 27/33, 60-572 Poznań, Poland.

ABSTRACT
Accumulating evidence suggests that certain features of hepatitis C virus (HCV), especially its high genetic variability, might be responsible for the low efficiency of anti-HCV treatment. Here, we present a bioinformatic analysis of HCV-1a populations isolated from 23 children with chronic hepatitis C (CHC) subjected to interferon-ribavirin therapy. The structures of the viral quasispecies were established based on a 132-amino-acid sequence derived from E1/E2 protein, including hypervariable region 1 (HVR1). Two types of HCV populations were identified. The first type, found in non-responders, contained a small number of closely related variants. The second type, characteristic for sustained responders, was composed of a large number of distantly associated equal-rank variants. Comparison of 445 HVR1 sequences showed that a significant number of variants present in non-responding patients are closely related, suggesting that certain, still unidentified properties of the pathogen may be key factors determining the result of CHC treatment.

Show MeSH
Related in: MedlinePlus