Characterization of Hepatitis C Virus genotype 3a Hypervariable region 1 in patients achieved rapid virological response to alpha interferon and Ribavirin Combination therapy

<p>Abstract</p> <p>Background</p> <p>Hepatitis C virus roots a chronic liver disease. Currently approved treatment strategy includes administration of alpha interferon and ribavirin combined therapy for 24-48 weeks. One of the predictor of sustained virological response is an early virological response to treatment characterized as rapid response. Hyper variable region 1 (HVR1) of E2 protein is responsible for viral entry and acts as a target for neutralizing antibodies. Any mutation in this region would effect virus interaction with target cell and viral persistence.</p> <p>Methods</p> <p>Thirty one clones of six pre-treatment samples subjected to combination therapy were investigated. Three of the patients were rapid responders (R1, R2 and R3) and two were breakthrough responders (BT1 and BT2). Envelope 2 gene was amplified, cloned and sequenced. Amino acid substitution, frequency, composition and antigenic properties of HVR 1 of E2 protein were studied.</p> <p>Results</p> <p>In both rapid responders (R.R) (14 amino acid sites) and breakthrough responders (BT.R) (13 amino acid sites) half of the amino acid sites were either conserved or resistant to any physiochemical change due to amino acid substitution. It also indicated that average composition of hydrophilic and basic amino acids were comparatively lower in rapid responders than other samples affecting probable interaction of virus with target cells. A central non antigenic region was constant among the breakthrough responders but differed in length significantly among rapid responders reflecting the adaptive nature of HVR1 to the immune response.</p> <p>Conclusions</p> <p>We observed that although HVR1is quite variable region in HCV 3a patients responding differently to treatment it still maintains its physiochemical properties for its proper functioning and viability.</p

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 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

Hepatitis C Treatment: current and future perspectives

Hepatitis C virus (HCV) is a member of Flaviviridae family and one of the major causes of liver disease. There are about 175 million HCV infected patients worldwide that constitute 3% of world's population. The main route of HCV transmission is parental however 90% intravenous drug users are at highest risk. Standard interferon and ribavirin remained a gold standard of chronic HCV treatment having 38-43% sustained virological response rates. Currently the standard therapy for HCV is pegylated interferon (PEG-INF) with ribavirin. This therapy achieves 50% sustained virological response (SVR) for genotype 1 and 80% for genotype 2 & 3. As pegylated interferon is expensive, standard interferon is still the main therapy for HCV treatment in under developed countries. On the other hand, studies showed that pegylated IFN and RBV therapy has severe side effects like hematological complications. Herbal medicines (laccase, proanthocyandin, Rhodiola kirilowii) are also being in use as a natural and alternative way for treatment of HCV but there is not a single significant report documented yet. Best SVR indicators are genotype 3 and 2, < 0.2 million IU/mL pretreatment viral load, rapid virological response (RVR) rate and age <40 years. New therapeutic approaches are under study like interferon related systems, modified forms of ribavirin, internal ribosome entry site (HCV IRES) inhibitors, NS3 and NS5a inhibitors, novel immunomodulators and specifically targeted anti-viral therapy for hepatitis C compounds. More remedial therapies include caspase inhibitors, anti-fibrotic agents, antibody treatment and vaccines

Nucleotide identity and variability among different Pakistani hepatitis C virus isolates

<p>Abstract</p> <p>Background</p> <p>The variability within the hepatitis C virus (HCV) genome has formed the basis for several genotyping methods and used widely for HCV genotyping worldwide.</p> <p>Aim</p> <p>The aim of the present study was to determine percent nucleotide identity and variability in HCV isolates prevalent in different geographical regions of Pakistan.</p> <p>Methods</p> <p>Sequencing analysis of the 5'noncoding region (5'-NCR) of 100 HCV RNA-positive patients representing all the four provinces of Pakistan were carried out using ABI PRISM 3100 Genetic Analyzer.</p> <p>Results</p> <p>The results showed that type 3 is the predominant genotypes circulating in Pakistan, with an overall prevalence of 50%. Types 1 and 4 viruses were 9% and 6% respectively. The overall nucleotide similarity among different Pakistani isolates was 92.50% ± 0.50%. Pakistani isolates from different areas showed 7.5% ± 0.50% nucleotide variability in 5'NCR region. The percent nucleotide identity (PNI) was 98.11% ± 0.50% within Pakistani type 1 sequences, 98.10% ± 0.60% for type 3 sequences, and 99.80% ± 0.20% for type 4 sequences. The PNI between different genotypes was 93.90% ± 0.20% for type 1 and type 3, 94.80% ± 0.12% for type 1 and type 4, and 94.40% ± 0.22% for type 3 and type 4.</p> <p>Conclusion</p> <p>Genotype 3 is the most prevalent HCV genotype in Pakistan. Minimum and maximum percent nucleotide divergences were noted between genotype 1 and 4 and 1 and 3 respectively.</p

A Study of Active Chaman Fault System (CFS) using SRTM DEM

Chaman fault is a seismically active fault running over 850km in western region of Pakistan and Afghanistan. It is a major geological structure between Indian and Eurasian plates. Chaman fault is a strike slip fault which is slipping nearly at the rate of 10mm per year. This research includes the evaluation of lithological processes and neotectonics activity using Hypsometric Integral (HI). We calculated values of hypsometric integral using SRTM DEM with 90m spatial resolution in active region of Chaman Fault (CF) and in its locality. We analyzed different mean, minimum and maximum elevations using regular square grids and measured the degree of spatial distribution of HI using Local Indices (LI) of Spatial Autocorrelation (LISA). LISA provides auto correlation for the cluster analysis of hotspots and cold spots of HI values to discriminate uplifted and eroded regions. Full Tex

Remote Sensing Evaluation of Neotectonics in Potwar Plateau Lesser Himalyas Pakistan

The Potwar plateau was developed in subduction zone of lower Himalayan fold and thrust in the North West region. This study identifies topographic deformation and neotectonics activity using Digital Evaluation Model (DEM). The SRTM DEM having resolution of 90 m analyzes active tectonics in local drainage network. Standard algorithms and geomorphic indices are used to extract isobase maps, concavity, steepness and relative rates of uplift. The steepness index indicates the elevation of Potwar region. The variable rates of uplift, indicates surface deformation in different regions of Potwar plateau. Isobase maps indicate lithological distinctions and structures under the influence of neotectonics using geological maps. Landsat satellite imagery was used to indicate neotectonics activity over the spatial drainage network and streams corresponding to the longitudinal river profile analysis

Hepatitis C virus genotype 3a infection and hepatocellular carcinoma: Pakistan experience

AIM: To assess the association between chronic hepatitis C virus (HCV) infection and hepatocellular carcinoma (HCC) in Pakistan, and the genotype distribution among these HCC patients