A mutation in Genotype 3a patients may explain lack of response to standard of care treatment...

(Study in 6 genotype 3a patients from the Virology Journal which probably wouldn't garner much interest other than the fact that the authors suggests that a mutation involving the substitution of glutamine (Q) with Leucine (L) in the one of the 3 breakthrough responders in the study made the area in question identical to the same region in HCV genotype 1a - maybe one clue as to why treatment in G3 patients is tougher than G2. Because of the mutation, the HCV virus may have the same ability to evade the immune system that we see in genotype 1a patients - Chris)

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.

Author: Samia AfzalMuhammad IdreesMadiha AkranZunaira AwanBushra KhubaibMahwish AftabZareen FatimaSadaf BadarAbrar Hussain
Credits/Source: Virology Journal 2010, 7:377