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Analysis of mutations within the 5' untranslated region, interferon sensitivity region, and PePHD region as a function of response to interferon therapy in hepatitis C virus-infected patients in India.

ABSTRACT: Mutations in several subgenomic regions have been implicated in influencing response to interferon therapy; however, a comprehensive picture of Indian patients was lacking. Based on the viral load and clinical factors, 10 out of 15 patients were found to be complete responders, whereas 5 patients were nonresponders. The pretreatment viral RNA load of the patients was found to be between 5.20 and 6.13 log10 IU/ml, which eventually fell to 2.77 log10 IU/ml after 24 weeks of treatment, whereas in the case of nonresponders, the average was 5.38 log10 IU/ml. In order to study the influence of the hepatitis C virus genotype on the response to interferon therapy, the 5' untranslated region sequences of the samples were analyzed, which showed that genotype 3 patients responded better than genotype 1 patients. Additionally, the mutations in the interferon sensitivity-determining region (ISDR) of the NS5A protein and the double-stranded RNA-activated protein kinase-eukaryotic initiation factor 2 alpha phosphorylation homology domain (PePHD) of the E2 envelope protein, before and after treatment, were compared with nonresponder prototype J. Although, no clear correlation was found in the case of the mutated ISDR, some significant changes in residues were observed in the PePHD region, which could be helpful in understanding the molecular basis of resistance to therapy. Interestingly, analysis of the quasispecies variations showed a change in genotype in one sample during treatment, which might have contributed to the resistance. The results suggest that the mutations in different regions of the viral genome might have a concerted effect on the response to interferon therapy.

SUBMITTER: Gupta R

PROVIDER: S-EPMC1393096 | biostudies-literature | 2006 Mar

REPOSITORIES: biostudies-literature

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Analysis of mutations within the 5' untranslated region, interferon sensitivity region, and PePHD region as a function of response to interferon therapy in hepatitis C virus-infected patients in India.

Gupta Romi R Subramani Murugan M Khaja Mohammed N MN Madhavi Chandra C Roy Swagata S Habibullah Chittoor M CM Das Saumitra S

Journal of clinical microbiology 20060301 3

Mutations in several subgenomic regions have been implicated in influencing response to interferon therapy; however, a comprehensive picture of Indian patients was lacking. Based on the viral load and clinical factors, 10 out of 15 patients were found to be complete responders, whereas 5 patients were nonresponders. The pretreatment viral RNA load of the patients was found to be between 5.20 and 6.13 log10 IU/ml, which eventually fell to 2.77 log10 IU/ml after 24 weeks of treatment, whereas in t ...[more]

PMID: 16517843

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Project description:Mouse hepatitis virus (MHV), a member of the Coronaviridae, contains a polyadenylated positive-sense single-stranded genomic RNA which is 31 kb long. MHV replication and transcription take place via the synthesis of negative-strand RNA intermediates from a positive-strand genomic template. A cis-acting element previously identified in the 3' untranslated region binds to trans-acting host factors from mouse fibroblasts and forms at least three RNA-protein complexes. The largest RNA-protein complex formed by the cis-acting element and the lysate from uninfected mouse fibroblasts has a molecular weight of about 200 kDa. The complex observed in gel shift assays has been resolved by second-dimension sodium dodecyl sulfate-polyacrylamide gel electrophoresis into four proteins of approximately 90, 70, 58, and 40 kDa after RNase treatment. Specific RNA affinity chromatography also has revealed the presence of a 90-kDa protein associated with RNA containing the cis-acting element bound to magnetic beads. The 90-kDa protein has been purified from uninfected mouse fibroblast crude lysates. Protein microsequencing identified the 90-kDa protein as mitochondrial aconitase. Antibody raised against purified mitochondrial aconitase recognizes the RNA-protein complex and the 90-kDa protein, which can be released from the complex by RNase digestion. Furthermore, UV cross-linking studies indicate that highly purified mitochondrial aconitase binds specifically to the MHV 3' protein-binding element. Increasing the intracellular level of mitochondrial aconitase by iron supplementation resulted in increased RNA-binding activity in cell extracts and increased virus production as well as viral protein synthesis at early hours of infection. These results are particularly interesting in terms of identification of an RNA target for mitochondrial aconitase, which has a cytoplasmic homolog, cytoplasmic aconitase, also known as iron regulatory protein 1, a well-recognized RNA-binding protein. The binding properties of mitochondrial aconitase and the functional relevance of RNA binding appear to parallel those of cytoplasmic aconitase.

Dataset Information

Analysis of mutations within the 5' untranslated region, interferon sensitivity region, and PePHD region as a function of response to interferon therapy in hepatitis C virus-infected patients in India.

Publications

Analysis of mutations within the 5' untranslated region, interferon sensitivity region, and PePHD region as a function of response to interferon therapy in hepatitis C virus-infected patients in India.

Similar Datasets

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