IRES complexity before IFN‐alpha treatment and evolution of the viral load at the early stage of treatment in peripheral blood mononuclear cells from chronic hepatitis C patients

Thélu, M.A.; Leroy, Vincent; Ramzan, Muhammad; Dufeu‐Duchesne, Tania; Marche, Patrice N.; Zarski, Jean–Pierre

doi:10.1002/jmv.20792

Cited by 7 publications

(7 citation statements)

References 60 publications

(63 reference statements)

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“…Predictive folding however, revealed no effect of this mutation on the calculated thermodynamic stability. The role of nucleotide 243 in maintaining IRES structure was reported in HCV genotype 1b [21] and changes at this position were encountered in patients with viral stabilization. In genotype 1b, A243 pairs with U149, which is lacking in 4a, leading to altered pairing and explains the high rate of mutations at this position in our study population regardless of response to IFNα, thus making it more vulnerable to mutational event in genotype 4a.…”

Section: Discussionmentioning

confidence: 99%

“…Although genomic variability in HCV IRES was shown as one mechanism for escaping IFNα effects, there has been www.wjgnet.com controversy with regard to the predictive value of pretreatment IRES genomic variations in determining later response to IFNα [20] . Although domain Ⅲ harbors only 22% of the overall IRES mutations in a mixed genotype population [21] , IRES activity seems to depend more on the location of mutant nucleotides which play the most important roles in IRES activity.…”

Section: Discussionmentioning

confidence: 99%

“…This approach allowed us to minimize quasispecies complexity (mean of 2 variants/patient) compared with 7 or more variants/ patient in other studies [21] and to pinpoint a number of important genomic determinants of response to IFNα. Cloning of domain Ⅲ and sequencing of 15 clones in each patient allowed us to identify the major variant (identical sequences in 12 clones or more) in each patient so that noise was reduced during extrapolation of the relationship between genomic variation and treatment outcome.…”

Section: Discussionmentioning

confidence: 99%

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Positional effect of mutations in 5'UTR of hepatitis C virus 4a on patients' response to therapy

Awady¹,

Azzazy²,

Fahmy³

et al. 2009

WJG

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AIM:To investigate the effects of mutations in domain Ⅲ of the hepatitis C virus (HCV) internal ribosome entry sequences (IRES) on the response of chronic HCV genotype 4a patients to interferon therapy. METHODS:HCV RNA was extracted from 19 chronic HCV 4a patients receiving interferon/ribavirin therapy who showed dramatic differences in their response to combination therapy after initial viral clearance. IRES domain Ⅲ was cloned and 15 clones for each patient were sequenced. The obtained sequences were aligned with genotype 4a prototype using the ClustalW program and mutations scored. Prediction of stem-loop secondary structure and thermodynamic stability of the major quasispecies in each patient was performed using the MFOLD 3.2 program with Turner energies and selected constraints on base pairing. RESULTS:Analysis of RNA secondary structure revealed that insertions in domain Ⅲ altered WatsonCrick base pairing of stems and reduced molecular stability of RNA, which may ultimately reduce binding affinity to ribosomal proteins. Insertion mutations in domain Ⅲ were statistically more prevalent in sustained viral response patients (SVR, n = 14) as compared to breakthrough (BT, n = 5) patients. CONCLUSION:The influence of mutations within domain Ⅲ on the response of HCV patients to combination therapy depends primarily on the position, but not the frequency, of these mutations within IRES domain Ⅲ.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Positional effect of mutations in 5'UTR of hepatitis C virus 4a on patients' response to therapy

Awady¹,

Azzazy²,

Fahmy³

et al. 2009

WJG

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“…These changes in nucleotide may have dramatic effect on translation [Van et al, 2004]. Some studies reported that nucleotide changes in IRES region have influence on response to therapy [Th elu et al, 2007].…”

Section: Introductionmentioning

confidence: 99%

Optimum predictors of therapeutic outcome in HCV patients in Pakistan

Aziz

Raza

Irfan

2015

Journal of Medical Virology

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Hepatitis C virus (HCV) constitutes a major public health issue in Pakistan. Interferon α and ribavirin is used widely in routine practice in HCV infected patients in Pakistan.Treatment prediction is an important tool in therapy management. The present study aims to evaluate trends of predictive variables of treatment outcome in patients with different genotypes. The analysis comprised of 921 patients infected with different HCV genotypes. All the patients received IFN α-2b combined with ribavirin for 24 weeks. Overall, 60.2% patients achieved Sustained virologic response (SVR). In females sustained virologic response (SVR) was higher in age group <40 years (77.2%) than ≥40-50 years (60%) but in male SVR was almost equal in both age groups. We also found higher SVR with low pretreatment viral load (72.4%, P < 0.0001). Sustained Virologic Response in genotype 3a was 63.1%, 3b was 55%, 1a was 36.3% and 1b was 35% 3a +3b was 55.0% and 1a+3a was 42.9%. According to multivariable logistic regression analysis age < 40 years (2.0; 95%CI, 1.49-2.84; P = 0.0001), low pretreatment RNA level<800,000 IU/ml (4.0; 95%CI, 2.64-6.17; P = 0.0001), early virologic response at week 12 (12.3; 95%CI, 8.18-18.58; P < 0.0001) and non-fatty liver (2.5; 95%CI, 3.6-6.2; P = 0.005) showed significance for SVR. Nucleotide substitution in 5'UTR before treatment failed to show any characteristic pattern that has correlation with sustained response. Subtype 3a showed 95% presence among patients with age <40 years while older patients showed 79.9%.

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“…While HCV is mainly hepatotropic, cells of the lymphoid system constitute a secondary site of replication and lymphotropic variants often differ from those circulating in blood [7, 12, 13, 20, 21]. Several studies have shown that sequence changes within the 5′UTR affect the stability of secondary RNA structures and that they affect viral translation and replication efficiency; in addition, they are likely to determine viral tropism to particular cell compartments [2, 3, 5–7, 14, 22].…”

Section: Discussionmentioning

confidence: 99%

Analysis of Genotype 1b Hepatitis C Virus IRES in Serum and Peripheral Blood Mononuclear Cells in Patients Treated with Interferon and Ribavirin

Bukowska-Ośko

Cortés

Płoski

et al. 2014

BioMed Research International

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Hepatitis C virus (HCV) highly conserved IRES (internal ribosome entry site) sequence, localized within the 5′-untranslated region (5′UTR), may determine viral properties like replication efficiency and cell tropism. The aim of the present study was to characterize newly emerging 5′UTR variants in serum and peripheral blood mononuclear cells (PBMC) in chronic hepatitis C patients treated with interferon (IFN) and ribavirin and to identify their effect on IRES secondary structures. The study group consisted of 87 patients infected with genotype 1b from whom serum and PBMC samples were collected at 9 time points (before, during, and after treatment). New 5′UTR variants developed in 9 patients. Out of the overall 14 new variants, 9 (64%) were found in PBMC. HCV variants with decreased thermodynamic stability were identified only in PBMC and C183U mutation was the most common one in this compartment. In conclusion, antiviral treatment may favor emergence of new 5′UTR variants both in blood and in PBMC compartments. However, variants developing in the latter compartment were predicted to have lower thermodynamic stability of the IRES secondary structures compared to serum strains. C-U change in position 183, which has not been described previously, might indicate viral adaptation to lymphoid cells.

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IRES complexity before IFN‐alpha treatment and evolution of the viral load at the early stage of treatment in peripheral blood mononuclear cells from chronic hepatitis C patients

Cited by 7 publications

References 60 publications

Positional effect of mutations in 5'UTR of hepatitis C virus 4a on patients' response to therapy

Positional effect of mutations in 5'UTR of hepatitis C virus 4a on patients' response to therapy

Optimum predictors of therapeutic outcome in HCV patients in Pakistan

Analysis of Genotype 1b Hepatitis C Virus IRES in Serum and Peripheral Blood Mononuclear Cells in Patients Treated with Interferon and Ribavirin

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