MxA expression as marker for assessing the therapeutic response in HCV genotype 4 Egyptian patients (original) (raw)
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Gastroenterology Research, 2017
Background: Pegylated interferon (PegIFN) is used in the treatment of chronic hepatitis C virus (HCV) patients especially in resource limited countries. Treatment with PegIFN stimulates the expression of a number of host genes encoding enzymes with antiviral activities, including myxovirus resistance gene-A (MxA gene). MxA gene was found to have a single nucleotide polymorphism (SNP) at position-88 in the promoter region that affects the expression of MxA gene protein and was suggested to affect the treatment outcome. The aim of the work was to assess the relation between the SNP in the MxA gene and its impact on treatment of chronic HCV patients with PegIFN and ribavirin. Methods: We therefore genotyped the biallelic G/T SNP in the promoter region of MxA gene at position-88 from the transcription start site by restriction fragment length polymorphism (RFLP) in 70 chronic HCV genotype 4 interferon naive Egyptians and 40 healthy controls. Results: G allele was the prevalent one in both HCV patients group (105, 74.5%) and control group (66, 82.5%), while T allele was less expressed in patients group (36, 25.5%) and control group (14, 17.5%). There is no correlation between genotypes and response to IFN-alpha therapy:
African Journal of Biotechnology, 2011
Interferon used in the treatment of hepatitis C virus (HCV) patients stimulates the expression of a number of host genes encoding enzymes with antiviral activities, including myxovirus resistance gene-1 (Mx1). Mx1 gene was found to have a single nucleotide polymorphism (SNP) at position-88 in the promotor region that affect the expression of Mx 1 protein and was suggested to be associated with the response of HCV. In this study, we assessed the relation between the SNP in the Mx1 gene and the responsiveness of Egyptian HCV patients to pegylated interferon and ribavirin treatment along with other host-related and virus-related predictors of treatment outcome. We genotyped the biallelic G/T SNP in the promoter region of Mx1 gene at position-88 from the transcription start site by restriction fragment length polymorphism (RFLP) in 42 interferon treatment-naïve Egyptian patients that were treated with pegylated interferon and ribavirin. We found that Mx1 nt-88 SNP is not significantly correlated to achieving sustained virological response (SVR) after pegylated interferon alpha and ribavirin combined treatment. We conclude that Mx1 gene polymorphism at codon nt-88 cannot be considered as biological marker to potentially identify responders and non-responders of HCV patients to achieve a sustained virological response to treatment with interferon (IFN) in combination with ribavirin.
African Journal of …, 2011
Interferon used in the treatment of hepatitis C virus (HCV) patients stimulates the expression of a number of host genes encoding enzymes with antiviral activities, including myxovirus resistance gene-1 (Mx1). Mx1 gene was found to have a single nucleotide polymorphism (SNP) at position -88 in the promotor region that affect the expression of Mx 1 protein and was suggested to be associated with the response of HCV. In this study, we assessed the relation between the SNP in the Mx1 gene and the responsiveness of Egyptian HCV patients to pegylated interferon and ribavirin treatment along with other host-related and virus-related predictors of treatment outcome. We genotyped the biallelic G/T SNP in the promoter region of Mx1 gene at position -88 from the transcription start site by restriction fragment length polymorphism (RFLP) in 42 interferon treatment-naïve Egyptian patients that were treated with pegylated interferon and ribavirin. We found that Mx1 nt-88 SNP is not significantly correlated to achieving sustained virological response (SVR) after pegylated interferon alpha and ribavirin combined treatment. We conclude that Mx1 gene polymorphism at codon nt-88 cannot be considered as biological marker to potentially identify responders and non-responders of HCV patients to achieve a sustained virological response to treatment with interferon (IFN) in combination with ribavirin.
Journal of Gastroenterology and Hepatology, 1994
The polymerase chain reaction (PCR) was used to examine expression of interferon-alpha (IFN A) genes in general and the expression of messenger RNA (mRNA) encoding the subtypes IFN-a-2 and IFN-a-4 in blood and liver biopsy samples from patients with chronic hepatitis C or hepatitis non-A, non-B (HC/HNANB) infection entered into a trial of IFN-a-2a therapy. Peripheral blood mononuclear cells (PBMC) from healthy controls and HC/HNANB infected patients were studied for their capacity to produce transcripts encoding IFN-a after stimulation with Sendai virus. Expression at the level of mRNA for IFN A and the subtypes IFN A2 and A4 was detected in both controls and HC/HNANB infected patients PBMC and no significant difference was seen in expression of IFN A transcripts or level of total IFN-a secreted into culture supernatants between controls and patients. Interferon A, and specifically IFN A2 and IFN A4 transcripts were detected in a high proportion of liver biopsies from patients with HC/HNANB infection. The presence of IFN A mRNA (and specifically IFN A2 and IFN A4) showed no correlation to histological improvement nor response to therapy. The use of PCR to detect those IFN A genes that are not expressed, thereby identifying subtypes that may be lacking, could be the key to the choice of IFN-a subtypes that are used for effective therapy.
Journal of Medical Virology, 2000
Hepatitis C virus (HCV) infection causes acute and often chronic liver disease. The treatment of choice is interferon-␣ (IFN-␣). The proportion of patients responding to therapy in terms of a sustained virological response, however, is relatively low. One possible reason for the lack of effectiveness might be neutralization of the drug by host's inhibitory factors. Recent kinetic studies suggested that high doses of IFN-␣, especially during the initial phase of therapy, might improve the virological response rates. Eighteen patients infected chronically with HCV were treated with IFN-␣ either at a standard dose (3 × 10 6 to 6 × 10 6 IU IFN-␣ three times weekly) for 6 to 12 months or with an intensified therapy (6 × 10 6 IU IFN-␣ daily) for at least one month. As surrogate parameter for the intracellular effect of the drug, MxA gene expression was quantified in RNA preparations from peripheral blood mononuclear cells. Beta-2-microglobulin ( 2 M) concentrations were measured in serum. Serum HCV RNA titers were monitored in parallel. When compared to healthy individuals, untreated patients infected chronically with HCV were found to express 2.8-fold higher amounts of MxA specific transcripts. MxA gene expression and serum ß 2 M concentrations were found to be induced after administration of IFN-␣, independent of the virological response not only during the initial phase of the intensified therapy but also over several months during standard therapy. It is concluded from these results that both early non-effectiveness of high dose IFN-␣ therapy as well as long-term non-effectiveness of standard therapy are not due to IFN-␣ inhibitory or neutralizing elements in serum.
Journal of Medical Virology, 1995
The use of two new assays was evaluated for predicting the response to interferon (IFN) therapy in patients with chronic hepatitis C. The genotype of hepatitis C virus (HCV) was established by an enzyme-linked immunosorbent assay based on genotype-specific recombinant peptides of the NS4 region (genotyping ELISA). The concentration of HCV RNA was measured by a branched DNA assay (bDNA assay). Seventyeight patients received the same regimen of IFNa2a. Of the 74 patients assessed who completed the program, 38 (51.4%) were responders; i.e., their serum aminotransferase levels remained normal for 6 months or longer after stopping IFN, while 36 (48.6%) were nonresponders. The results of the HCV genotype determined by the genotyping ELISA and by the polymerase chain reaction (PCR) assay based on genotypespecific primers were similar. The serum concentrations of HCV RNA as measured by the bDNA assay and by the competitive PCR assay correlated closely and significantly (r = 0.82, P < 0.001 1. Multiple logistic regression analysis showed that the serum concentration of HCV RNA determined by the bDNA assay, the HCV genotype determined by the genotyping ELISA, and the histology activity index (HAI) of the liver were independently associated with IFN efficacy.
Journal of Infectious Diseases, 1998
Hepatitis C virus (HCV) RNA serum concentration, quasispecies complexity, and sequence and phylogenetic analysis of the nonstructural 5A gene (NS5A) interferon sensitivity determining region (ISDR) were determined in pretreatment serum samples from 47 patients with chronic hepatitis C (36 infected by HCV genotype 1b and 11 by 3a). Among HCV genotype 1b-infected patients, virus load was lower (P Å .003) and the number of NS5A-ISDR amino acid changes was higher (P Å .001) in long-term responders than in non-long-term responders, but there were no differences in quasispecies complexity. Multivariate analysis showed a close association between response to interferon and NS5A-ISDR phenotype. Phylogenetic analysis showed that isolates from non-long-term responders clustered apart from the majority of isolates from long-term responders. There was no association between virologic features and therapeutic response in HCV genotype 3a-infected patients. In conclusion, low virus load and mutant NS5A-ISDR phenotype are closely associated with long-term response to interferon in HCV genotype 1b-but probably not in 3a-infected patients. Hepatitis C virus (HCV), a member of the Flaviviridae fam-12], virus load [13-18], or both [8, 19, 20], and quasispecies complexity [21-26] of HCV have been identified as important ily, has a positive-sense, single-stranded RNA of Ç9.500 nucleotides [1] and is a major etiologic agent of chronic hepatitis determinants of the response. A clear influence on the response to interferon has recently been associated with sequence vari-worldwide [2-4]. Chronic hepatitis resulting from chronic HCV infection may lead to severe diseases, such as hepatic ability in the so-called interferon sensitivity determining region (ISDR) of the nonstructural 5A (NS5A) gene of HCV in pa-cirrhosis and hepatocellular carcinoma [5, 6]. Interferon-a administration is the only licensed therapy for tients from Japan infected by genotype 1b [27-33] or 2 [33, 34], but such association has not been described in European chronic hepatitis C, but the effectiveness of this treatment is highly variable. A minority of patients present a long-term patients infected by genotype 1b [35-37] or 3a [36]. Thus, the prognostic relevance of such a putative NS5A-ISDR remains response to low doses of interferon [7], whereas many others do not satisfactorily respond to high or to increasing doses of controversial. In this study, HCV RNA titer, quasispecies complexity, and this drug [8, 9], indicating that a different degree of sensitivity to interferon exists among HCV-infected persons. Early studies NS5A-ISDR sequence diversity were determined in pretreatment serum samples from patients infected with HCV geno-showed that responsiveness to interferon appeared to be related to several host factors, such as patient age and sex, duration types 1b and 3a, who received a 6-month course of standard interferon-a therapy. The relationship between virologic data, of infection, iron deposition, and liver fibrosis [10]. More recent evidence suggests that factors related to the infecting virus patient characteristics, and therapeutic results was analyzed. itself are closely involved. Among the latter, genotype [11, Patients and Methods
Interferon type I gene expression in chronic hepatitis C
Laboratory Investigation, 2004
Hepatitis C virus (HCV) frequently causes chronic liver disease. The cause of viral persistence might be an inappropriate type I interferon (IFN) induction. To analyze the host's IFN response in chronic hepatitis C, we measured the transcription level of type I IFN genes as well as type I IFN-regulated genes in liver tissue and corresponding blood samples from patients with chronic hepatitis C, nonviral liver diseases, and a suspected but later excluded liver disease. Competitive and real-time RT-PCR assays were used to quantify the messenger RNA (mRNA) levels of all known IFN-a, IFN-b, and IFN-k genes and those of some IFN-regulated genes. We failed to detect any hepatic type I IFN mRNA induction, although liver tissue of chronic hepatitis C patients contained high numbers of some type I IFN-inducible effector mRNA molecules. Analysis of peripheral blood samples, however, showed a clear type I IFN induction. Parallel experiments employing HCV replicon cell lines revealed that replication of HCV RNA is not sufficient to induce any type I IFN nor to induce directly type I IFN-regulated genes such as MxA. In conclusion, our data provide evidence for the absence of an induction of type I IFN genes by HCV in the human liver and argue for a further development of type I IFN-based therapies.
Advances in Infectious Diseases, 2013
We aim to determine the baseline factors associated with partial and cEVR by analyzing the data of 1861 Egyptian patients treated for 12 weeks with a course of Peg-IFN plus RBV. Base line data of 1861 Egyptian patients with chronic hepatitis C coming at Cairo-Fatemic Hospital for HCV treatment were studied including full clinical, Ultrasonographic examination, laboratory evaluation and liver biopsy. The most significant variables in relation to complete early virological response were low Hb level (<13 gm/dl) with p < 0.01, the stage of fibrosis p value < 0.05 and the grades of inflammation p value < 0.05 were associated with less achievement of c EVR. We conclude that identifying the most significant predictors of response such as Hb, stage of fibrosis F, at baseline before initiating treatment is mandatory to predict which patient will be more expected to achieve a cEVR and thus reducing the side-effects and healthcare costs associated with interferon therapies.