Hepatitis C virus genotype 1a NS5A pretreatment sequence variation and viral kinetics in African American and white patients.
ABSTRACT In hepatitis C virus (HCV) infection, race is a determinant of treatment response and interferon (IFN) effectiveness. Here, we investigated whether there were differences in the pretreatment viral strains between African American patients and white patients and whether these differences correlated with viral kinetics. IFN effectiveness was calculated using a viral kinetic model. The HCV NS5A region from 21 treated patients with HCV genotype 1a was sequenced and analyzed. White patients displayed more mutations in the V3 region (mean+/-SD, 4.5+/-1.4 vs. 2.9+/-1.6; P=.016), and treatment responders tended to have more mutations in this region than did nonresponders. There was a significant positive correlation between IFN effectiveness and the number of mutations in the V3 region (P=.03). There was no clustering of strains by race, treatment response, or IFN effectiveness in phylogenetic analyses. The results of this study, in conjunction with those of a previous study illustrating the impaired IFN effectiveness in African Americans, suggest a role for host-related factors.
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ABSTRACT: Viral diversity is an important predictor of hepatitis C virus (HCV) treatment response and may influence viral pathogenesis. HIV influences HCV variability in the plasma; however, limited data on viral variability are available from distinct tissue/cell compartments in patients co-infected with HIV and HCV. Thus, this exploratory study evaluated diversity of the hypervariable region 1 (HVR1) of HCV in the plasma and liver for 14 patients co-infected with HIV and HCV. Median intra-patient genetic distances and entropy values were similar in the plasma and liver compartments. Positive immune selection pressure was observed in the plasma for five individuals and in the liver for three individuals. Statistical evidence supporting viral compartmentalization was found in five individuals. Linear regression identified ALT (P = 0.0104) and AST (P = 0.0130) as predictors of viral compartmentalization. A total of 12 signature amino acids that distinguish liver from plasma E1/HVR1 were identified. One signature amino acid was shared by at least two individuals. These findings suggest that HCV compartmentalization is relatively common among patients co-infected with HIV and HCV. These data also imply that evaluating viral diversity, including drug resistance patterns, in the serum/plasma only may not adequately represent viruses replicating with in the liver and, thus, deserves careful consideration in future studies. J. Med. Virol. © 2014 Wiley Periodicals, Inc.Journal of Medical Virology 04/2014; · 2.37 Impact Factor
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ABSTRACT: Hepatitis C virus (HCV) is a major cause of liver disease worldwide. HCV is able to evade host defense mechanisms, including both innate and acquired immune responses, to establish persistent infection, which results in a broad spectrum of pathogenicity, such as lipid and glucose metabolism disorders and hepatocellular carcinoma development. The HCV genome is characterized by a high degree of genetic diversity, which can be associated with viral sensitivity or resistance (reflected by different virological responses) to interferon (IFN)-based therapy. In this regard, it is of importance to note that polymorphisms in certain HCV genomic regions have shown a close correlation with treatment outcome. In particular, among the HCV proteins, the core and nonstructural proteins (NS) 5A have been extensively studied for their correlation with responses to IFN-based treatment. This review aims to cover updated information on the impact of major HCV genetic factors, including HCV genotype, mutations in amino acids 70 and 91 of the core protein and sequence heterogeneity in the IFN sensitivity-determining region and IFN/ribavirin resistance-determining region of NS5A, on virological responses to IFN-based therapy.World journal of gastroenterology : WJG. 06/2014; 20(24):7555-7569.
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ABSTRACT: Hepatitis C virus (HCV) is considered a significant risk factor in HCV-induced liver diseases and development of hepatocellular carcinoma (HCC). Nucleotide substitutions in the viral genome result in its diversification into quasispecies, subtypes and distinct genotypes. Different genotypes vary in their infectivity and immune response due to these nucleotide/amino acid variations. The current combination treatment for HCV infection is pegylated interferon α (PEG-IFN-α) with ribavirin, with a highly variable response rate mainly depending upon the HCV genotype. Genotypes 2 and 3 are found to respond better than genotypes 1 and 4, which are more resistant to IFN-based therapies. Different studies have been conducted worldwide to explore the basis of this difference in therapy response, which identified some putative regions in the HCV genome, especially in Core and NS5a, and to some extent in the E2 region, containing specific sequences in different genotypes that act differently with respect to the IFN response. In the review, we try to summarize the role of HCV proteins and their nucleotide sequences in association with treatment outcome in IFN-based therapy.Archives of Virology 07/2013; · 2.03 Impact Factor