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Occurrence of genetic modifications in core, 5'UTR and NS5b of HCV associated with viral response to treatment.

Kanwal S, Mahmood T - Virol. J. (2014)

Bottom Line: At nucleotide and amino acid level, the genetic distance and mutation, number of predicted N-phosphorylation and N-glycosylation sites was higher in group 2 as compared to group 1.It can be concluded that heterogeneity both at nucleotide and amino acid level contributed in developing drug resistant phenotype.Furthermore, prediction of phosphorylation and glycosylation sites could help in targeting the proper sites for drug designing.

View Article: PubMed Central - PubMed

Affiliation: Department of Plant Sciences, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan. tmahmood.qau@gmail.com.

ABSTRACT

Background: It is becoming progressively more understandable that genetic variability of viruses is a major challenge in translating the laboratory findings to clinic. Genetic variability is the underlying cause of variant viral proteins which are not targetable by host immunological machinery.

Methods: 500 patients were enrolled in study and amongst them, 451 patients were followed and categorized into two groups on the basis of their treatment response. Group 1 consisting of the 376 patients exhibited SVR while group 2 comprised 75 patients who were non-responders on the basis of viral load as evidenced by Real-Time PCR. Comparative sequence analysis was done between 75 non-responders and 75 responders (randomly picked from 376) by targeting three genomic regions, 5'UTR, core and NS5B and amplified products were directly sequenced and obtained sequences were cleaned, aligned and submitted to GenBank. Maximum Parsimony (MP) method was used for phylogenetic analysis and dendrograms were dragged using MEGA 5. Heterogeneity at nucleotide and amino acid level was determined using software BioEdit and DNAman while phosphorylation and N-linked glycosylation sites were determined using NetPhos 2.0 and SignalP-NN.

Results: Genotype 3 was prevalent in group 1 whereas non-responders indicated rare genotypes of Pakistan i.e. 4 and 5, genotype 6q and 6v were reported first time from Pakistan in this study. At nucleotide and amino acid level, the genetic distance and mutation, number of predicted N-phosphorylation and N-glycosylation sites was higher in group 2 as compared to group 1. Difference in percentage composition of individual amino acids was noted to be different between the two groups.

Conclusions: It can be concluded that heterogeneity both at nucleotide and amino acid level contributed in developing drug resistant phenotype. Moreover, occurrence of rare genotypes might hurdle the way to positive response of conventional treatment. Furthermore, prediction of phosphorylation and glycosylation sites could help in targeting the proper sites for drug designing.

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Related in: MedlinePlus

Representative output of DNAman. Amino acid substitution in the study sequences in comparison to the reference sequences obtained from DNAman.
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Fig9: Representative output of DNAman. Amino acid substitution in the study sequences in comparison to the reference sequences obtained from DNAman.

Mentions: The output of the MEGA 5 and DNAman revealed that total number of conserved and variable sites was considerably different in both treatment groups with the difference in amino acid positions. The conserved amino acid positions in SVR patients showed substitution in amino acids in non-responders (Table 3). Multiple amino acid substitution at single site was more common in non-responders than in SVR patients for example at position 1 and 4 amino acids histidine and threonine were replaced by four other amino acids in non-responders whereas in SVR patients at these positions single substitutions were observed. Graphical output of some of the amino acid substitution is given in the Figure 9.Table 3


Occurrence of genetic modifications in core, 5'UTR and NS5b of HCV associated with viral response to treatment.

Kanwal S, Mahmood T - Virol. J. (2014)

Representative output of DNAman. Amino acid substitution in the study sequences in comparison to the reference sequences obtained from DNAman.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4289283&req=5

Fig9: Representative output of DNAman. Amino acid substitution in the study sequences in comparison to the reference sequences obtained from DNAman.
Mentions: The output of the MEGA 5 and DNAman revealed that total number of conserved and variable sites was considerably different in both treatment groups with the difference in amino acid positions. The conserved amino acid positions in SVR patients showed substitution in amino acids in non-responders (Table 3). Multiple amino acid substitution at single site was more common in non-responders than in SVR patients for example at position 1 and 4 amino acids histidine and threonine were replaced by four other amino acids in non-responders whereas in SVR patients at these positions single substitutions were observed. Graphical output of some of the amino acid substitution is given in the Figure 9.Table 3

Bottom Line: At nucleotide and amino acid level, the genetic distance and mutation, number of predicted N-phosphorylation and N-glycosylation sites was higher in group 2 as compared to group 1.It can be concluded that heterogeneity both at nucleotide and amino acid level contributed in developing drug resistant phenotype.Furthermore, prediction of phosphorylation and glycosylation sites could help in targeting the proper sites for drug designing.

View Article: PubMed Central - PubMed

Affiliation: Department of Plant Sciences, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan. tmahmood.qau@gmail.com.

ABSTRACT

Background: It is becoming progressively more understandable that genetic variability of viruses is a major challenge in translating the laboratory findings to clinic. Genetic variability is the underlying cause of variant viral proteins which are not targetable by host immunological machinery.

Methods: 500 patients were enrolled in study and amongst them, 451 patients were followed and categorized into two groups on the basis of their treatment response. Group 1 consisting of the 376 patients exhibited SVR while group 2 comprised 75 patients who were non-responders on the basis of viral load as evidenced by Real-Time PCR. Comparative sequence analysis was done between 75 non-responders and 75 responders (randomly picked from 376) by targeting three genomic regions, 5'UTR, core and NS5B and amplified products were directly sequenced and obtained sequences were cleaned, aligned and submitted to GenBank. Maximum Parsimony (MP) method was used for phylogenetic analysis and dendrograms were dragged using MEGA 5. Heterogeneity at nucleotide and amino acid level was determined using software BioEdit and DNAman while phosphorylation and N-linked glycosylation sites were determined using NetPhos 2.0 and SignalP-NN.

Results: Genotype 3 was prevalent in group 1 whereas non-responders indicated rare genotypes of Pakistan i.e. 4 and 5, genotype 6q and 6v were reported first time from Pakistan in this study. At nucleotide and amino acid level, the genetic distance and mutation, number of predicted N-phosphorylation and N-glycosylation sites was higher in group 2 as compared to group 1. Difference in percentage composition of individual amino acids was noted to be different between the two groups.

Conclusions: It can be concluded that heterogeneity both at nucleotide and amino acid level contributed in developing drug resistant phenotype. Moreover, occurrence of rare genotypes might hurdle the way to positive response of conventional treatment. Furthermore, prediction of phosphorylation and glycosylation sites could help in targeting the proper sites for drug designing.

Show MeSH
Related in: MedlinePlus