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.
abstract: 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.
authors.affiliation: National Centre of Excellence in Molecular Biology, 87-West Canal Bank Road Thokar Niaz Baig Lahore-53700, University of the Punjab, Lahore, Pakistan.
authors.forename: Samia
authors.initials: S
authors.lastname: Afzal
authors.forename: Muhammad
authors.initials: M
authors.lastname: Idrees
authors.forename: Madiha
authors.initials: M
authors.lastname: Akram
authors.forename: Zunaira
authors.initials: Z
authors.lastname: Awan
authors.forename: Bushra
authors.initials: B
authors.lastname: Khubaib
authors.forename: Mahwish
authors.initials: M
authors.lastname: Aftab
authors.forename: Zareen
authors.initials: Z
authors.lastname: Fatima
authors.forename: Sadaf
authors.initials: S
authors.lastname: Badar
authors.forename: Abrar
authors.initials: A
authors.lastname: Hussain
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D007372:Interferons / Q000627:therapeutic use*; D009154:Mutation / Q000235:genetics; D010154:Pakistan; D017434:Protein Structure, Tertiary; D012254:Ribavirin / Q000627:therapeutic use*; D016415:Sequence Alignment; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: D000998:Antiviral Agents; D015852:Eukaryotic Initiation Factor-2; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus; D012254:Ribavirin; D007372:Interferons