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Mutations in the E2-PePHD region of hepatitis C virus genotype-3a and correlation with response to interferon and ribavirin combination therapy in Pakistani patients

Hepatitis C is a major health problem affecting more than 200 million individuals in the world. Current treatment regimen consisting of interferon alpha and ribavirin does not always succeed in eliminating the virus completely from patient's body. One of the mechanisms by which virus evades the...

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Autores principales: Afzal, Samia, Idrees, Muhammad, Akram, Madiha, Awan, Zunaira, Khubaib, Bushra, Aftab, Mahwish, Fatima, Zareen, Badar, Sadaf, Hussain, Abrar
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3019161/
https://www.ncbi.nlm.nih.gov/pubmed/21194456
http://dx.doi.org/10.1186/1743-422X-7-377
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author Afzal, Samia
Idrees, Muhammad
Akram, Madiha
Awan, Zunaira
Khubaib, Bushra
Aftab, Mahwish
Fatima, Zareen
Badar, Sadaf
Hussain, Abrar
author_facet Afzal, Samia
Idrees, Muhammad
Akram, Madiha
Awan, Zunaira
Khubaib, Bushra
Aftab, Mahwish
Fatima, Zareen
Badar, Sadaf
Hussain, Abrar
author_sort Afzal, Samia
collection PubMed
description Hepatitis C is a major health problem affecting more than 200 million individuals in the world. Current treatment regimen consisting of interferon alpha and ribavirin does not always succeed in eliminating the virus completely from patient's body. One of the mechanisms by which virus evades the antiviral effect of interferon alpha involves protein kinase (PKR) eukaryotic initiation factor 2 alpha (eIF2a) phosphorylation homology domain (PePHD). This domain in genotype 1 strains is reportedly homologous to PKR and its target eIF2a. By binding to PKR, PePHD inhibits its activity and therefore cause virus to evade antiviral activity of interferon (IFN). Many studies have correlated substitutions in this domain to the treatment response and lead to inconclusive results. Some studies suggested that substitutions favor response while others emphasized that no correlation exists. In the present study we therefore compared sequences of PePHD domain of thirty one variants of six hepatitis C virus patients of genotype 3. Three of our HCV 3a infected patients showed rapid virological response to interferon alpha and ribavirin combination therapy whereas the remaining three had breakthrough to the same combination therapy. It is found that PePHD domain is not entirely conserved and has substitutions in some isolates irrespective of the treatment response. However substitution of glutamine (Q) with Leucine (L) in one of the breakthrough responders made it more identical to HCV genotype 1a. These substitutions in the breakthrough responders also tended to increase average hydrophilic activity thus making binding of PePHD to PKR and inhibition of PKR more favorable.
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spelling pubmed-30191612011-01-12 Mutations in the E2-PePHD region of hepatitis C virus genotype-3a and correlation with response to interferon and ribavirin combination therapy in Pakistani patients Afzal, Samia Idrees, Muhammad Akram, Madiha Awan, Zunaira Khubaib, Bushra Aftab, Mahwish Fatima, Zareen Badar, Sadaf Hussain, Abrar Virol J Short Report Hepatitis C is a major health problem affecting more than 200 million individuals in the world. Current treatment regimen consisting of interferon alpha and ribavirin does not always succeed in eliminating the virus completely from patient's body. One of the mechanisms by which virus evades the antiviral effect of interferon alpha involves protein kinase (PKR) eukaryotic initiation factor 2 alpha (eIF2a) phosphorylation homology domain (PePHD). This domain in genotype 1 strains is reportedly homologous to PKR and its target eIF2a. By binding to PKR, PePHD inhibits its activity and therefore cause virus to evade antiviral activity of interferon (IFN). Many studies have correlated substitutions in this domain to the treatment response and lead to inconclusive results. Some studies suggested that substitutions favor response while others emphasized that no correlation exists. In the present study we therefore compared sequences of PePHD domain of thirty one variants of six hepatitis C virus patients of genotype 3. Three of our HCV 3a infected patients showed rapid virological response to interferon alpha and ribavirin combination therapy whereas the remaining three had breakthrough to the same combination therapy. It is found that PePHD domain is not entirely conserved and has substitutions in some isolates irrespective of the treatment response. However substitution of glutamine (Q) with Leucine (L) in one of the breakthrough responders made it more identical to HCV genotype 1a. These substitutions in the breakthrough responders also tended to increase average hydrophilic activity thus making binding of PePHD to PKR and inhibition of PKR more favorable. BioMed Central 2010-12-31 /pmc/articles/PMC3019161/ /pubmed/21194456 http://dx.doi.org/10.1186/1743-422X-7-377 Text en Copyright ©2010 Afzal et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<url>http://creativecommons.org/licenses/by/2.0</url>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Short Report
Afzal, Samia
Idrees, Muhammad
Akram, Madiha
Awan, Zunaira
Khubaib, Bushra
Aftab, Mahwish
Fatima, Zareen
Badar, Sadaf
Hussain, Abrar
Mutations in the E2-PePHD region of hepatitis C virus genotype-3a and correlation with response to interferon and ribavirin combination therapy in Pakistani patients
title Mutations in the E2-PePHD region of hepatitis C virus genotype-3a and correlation with response to interferon and ribavirin combination therapy in Pakistani patients
title_full Mutations in the E2-PePHD region of hepatitis C virus genotype-3a and correlation with response to interferon and ribavirin combination therapy in Pakistani patients
title_fullStr Mutations in the E2-PePHD region of hepatitis C virus genotype-3a and correlation with response to interferon and ribavirin combination therapy in Pakistani patients
title_full_unstemmed Mutations in the E2-PePHD region of hepatitis C virus genotype-3a and correlation with response to interferon and ribavirin combination therapy in Pakistani patients
title_short Mutations in the E2-PePHD region of hepatitis C virus genotype-3a and correlation with response to interferon and ribavirin combination therapy in Pakistani patients
title_sort mutations in the e2-pephd region of hepatitis c virus genotype-3a and correlation with response to interferon and ribavirin combination therapy in pakistani patients
topic Short Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3019161/
https://www.ncbi.nlm.nih.gov/pubmed/21194456
http://dx.doi.org/10.1186/1743-422X-7-377
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