Variability of the Nonstructural 5A Protein of Hepatitis C Virus Type 3a Isolates and Relation to Interferon Sensitivity

Castelain, Sandrine; Khorsi, Hafida; Roussel, J; François, Clément; Jaillon, Olivier; Capron, Dominique; Pénin, François; Wychowski, Czeslaw; Meurs, Éliane; Duverlie, Gilles

doi:10.1086/339051

Cited by 22 publications

(26 citation statements)

References 62 publications

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“…Because both IRES activity in the initiation of translation and the ability to inhibit PKR are features that should favor viral infectivity and resistance to interferon-mediated host defence mechanisms, it is likely that there is strong selection pressure against any mutations that alter the structure of the HCV IRES (Soler et al 2002). Thus, in contrast to the situation for the viral protein NS5A (and perhaps E2; Taylor et al 1999;Chayama et al 2000;Cochrane et al 2000;Mihm et al 2000;Sarrazin et al 2000;Taylor et al 2000;Lo and Lin 2001;Podevin et al 2001;Sarrazin et al 2001;Castelain et al 2002), differences in the HCV IRES that alter its ability to regulate PKR may not be observed between viral strains because they may also impair the translational activity of the IRES (Laporte et al 2000). Conservation of secondary structure is likely to be important not only for the binding of PKR but also for recognition of the IRES by cellular protein factors required for the initiation of viral protein synthesis [e.g., polypeptide chain initiation factor eIF3 (Odreman-Macchioli et al 2000;Collier et al 2002), the 40S ribosomal subunit (Fukushi et al 1999(Fukushi et al , 2001Kolupaeva et al 2000;Kieft et al 2001;Spahn et al 2001;Lytle et al 2002), and the La antigen (Ali and Siddiqui 1997)].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the protein kinase PKR by the internal ribosome entry site of hepatitis C virus genomic RNA

Vyas

Elia²,

Clemens³

2003

RNA

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Translation of the hepatitis C genome is mediated by internal ribosome entry on the structurally complex 5 untranslated region of the large viral RNA. Initiation of protein synthesis by this mechanism is independent of the cap-binding factor eIF4E, but activity of the initiator Met-tRNA f -binding factor eIF2 is still required. HCV protein synthesis is thus potentially sensitive to the inhibition of eIF2 activity that can result from the phosphorylation of the latter by the interferon-inducible, double-stranded RNA-activated protein kinase PKR. Two virally encoded proteins, NS5A and E2, have been shown to reduce this inhibitory effect of PKR by impairing the activation of the kinase. Here we present evidence for a third viral strategy for PKR inhibition. A region of the viral RNA comprising part of the internal ribosome entry site (IRES) is able to bind to PKR in competition with double-stranded RNA and can prevent autophosphorylation and activation of the kinase in vitro. The HCV IRES itself has no PKR-activating ability. Consistent with these findings, cotransfection experiments employing a bicistronic reporter construct and wild-type PKR indicate that expression of the protein kinase is less inhibitory towards HCV IRES-driven protein synthesis than towards cap-dependent protein synthesis. These data suggest a dual function for the viral IRES, with both a structural role in promoting initiation complex formation and a regulatory role in preventing inhibition of initiation by PKR.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the protein kinase PKR by the internal ribosome entry site of hepatitis C virus genomic RNA

Vyas

Elia²,

Clemens³

2003

RNA

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“…Therefore, mutational analysis by sequencing the entire NS5A gene was performed to assess the significance of NS5A mutations outside the ISDR/PKR binding domain (14,28,98,124). In a study that reported the analysis of 70 full-length NS5A sequences, the overall number of mutations within the NS5A protein was highly correlated with the treatment response (124) ( Table 1).…”

Section: Vol 20 2007 Resistance To Treatment In Patients With Hcv 27mentioning

confidence: 99%

“…In a study that reported the analysis of 70 full-length NS5A sequences, the overall number of mutations within the NS5A protein was highly correlated with the treatment response (124) ( Table 1). Furthermore, in three studies, a local accumulation of mutations around the so-called variable region 3 (V3) within the carboxy-terminal part of the NS5A protein was found to correlate with the treatment response in HCV genotype 1a/1b isolates, which is currently under further investigation (14,98,124). Furthermore, it must be assumed that additional mutations outside the NS5A gene but within other genes of the HCV open reading frame are important for determinations of IFN-␣ sensitivity.…”

Section: Vol 20 2007 Resistance To Treatment In Patients With Hcv 27mentioning

confidence: 99%

Viral Determinants of Resistance to Treatment in Patients with Hepatitis C

2007

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SUMMARY Chronic hepatitis C virus (HCV) infection affects more than 170 million persons worldwide and is responsible for the development of liver cirrhosis in many cases. Standard treatment with pegylated alpha interferon (IFN-α) in combination with the nucleoside analogue ribavirin leads to a sustained virologic response in approximately half of the patients. IFN-α is classified as an indirect treatment, as it interacts with the host's immune response. The mechanism of action of ribavirin is still unknown. The benefit of triple therapy by adding other antiviral agents, e.g., amantadine, is controversial. Currently, new direct antiviral drugs (HCV protease/polymerase inhibitors) are being evaluated in phase 1/phase 2 trials. Phenotypic resistance to antiviral therapy has been attributed to amino acid variations within distinct regions of the HCV polyprotein. While sensitivity to IFN-α-based antiviral therapy in vivo is clearly correlated with the number of mutations within the HCV NS5A protein, the underlying functional mechanisms for this association are unknown. In turn, in vitro, several mechanisms to circumvent the host immune defense or to block treatment-induced antiviral activities have been described for different HCV proteins. By the introduction of direct antiviral drugs, hepatitis C therapy now is entering a new era in which the development of resistance may become the most important parameter for treatment success or failure.

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“…However, studies of HCV genotype 2b and 3a did not find such a relation between SVR and NS5A variability (8,89). Additionally, no binding between PKR and the genotype 3a NS5A from the IFN-resistant HCV strains was observed in vitro (20).…”

mentioning

confidence: 98%

Coevolution of the Hepatitis C Virus Polyprotein Sites in Patients on Combined Pegylated Interferon and Ribavirin Therapy

Lara

Xia

Purdy

et al. 2011

J Virol

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Genotype-specific sensitivity of the hepatitis C virus (HCV) to interferon-ribavirin (IFN-RBV) combination therapy and reduced HCV response to IFN-RBV as infection progresses from acute to chronic infection suggest that HCV genetic factors and intrahost HCV evolution play important roles in therapy outcomes. HCV polyprotein sequences (n ‫؍‬ 40) from 10 patients with unsustainable response (UR) (breakthrough and relapse) and 10 patients with no response (NR) following therapy were identified through the Virahep-C study. Bayesian networks (BNs) were constructed to relate interrelationships among HCV polymorphic sites to UR/NR outcomes. All models showed an extensive interdependence of HCV sites and strong connections (P < 0.003) to therapy response. Although all HCV proteins contributed to the networks, the topological properties of sites differed among proteins. E2 and NS5A together contributed ϳ40% of all sites and ϳ62% of all links to the polyprotein BN. The NS5A BN and E2 BN predicted UR/NR outcomes with 85% and 97.5% accuracy, respectively, in 10-fold cross-validation experiments. The NS5A model constructed using physicochemical properties of only five sites was shown to predict the UR/NR outcomes with 83.3% accuracy for 6 UR and 12 NR cases of the HALT-C study. Thus, HCV adaptation to IFN-RBV is a complex trait encoded in the interrelationships among many sites along the entire HCV polyprotein. E2 and NS5A generate broad epistatic connectivity across the HCV polyprotein and essentially shape intrahost HCV evolution toward the IFN-RBV resistance. Both proteins can be used to accurately predict the outcomes of IFN-RBV therapy.Hepatitis C virus (HCV) is the major etiologic agent of blood-borne non-A, non-B hepatitis (25). Chronic HCV infection is an established risk factor for the development of liver diseases, such as fibrosis, cirrhosis, and hepatocellular carcinoma (33,124,125). Approximately 70% to 80% of HCVinfected patients fail to clear the virus and progress to chronicity (89a). At present, there are no preventive vaccines against HCV. The current, accepted therapeutic approach to treating chronic hepatitis C infection involves a 24-or 48-week course of pegylated alpha interferon (IFN-␣) combined with ribavirin (RBV) (i.e. IFN-RBV therapy) (48, 52). Because only 50% to 70% of chronically infected patients develop a sustained virologic response (SVR) to this treatment (48,52,55,80) and because patient intolerance to such therapy is common (61, 68, 120), the development and application of other therapeutic approaches using antiviral compounds that act against HCV more efficaciously and yet generate lower rates of adverse effects are major clinical management and public health objectives. Therapeutic failure presents in two forms: (i) complete resistance to treatment (no response [NR]) and (ii) unsustainable response (UR), which is characterized by an increase in HCV load observed during therapy after an initial period of decline in viral load (breakthrough) or observed after cessation of therapy (relapse)...

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Variability of the Nonstructural 5A Protein of Hepatitis C Virus Type 3a Isolates and Relation to Interferon Sensitivity

Cited by 22 publications

References 62 publications

Inhibition of the protein kinase PKR by the internal ribosome entry site of hepatitis C virus genomic RNA

Inhibition of the protein kinase PKR by the internal ribosome entry site of hepatitis C virus genomic RNA

Viral Determinants of Resistance to Treatment in Patients with Hepatitis C

Coevolution of the Hepatitis C Virus Polyprotein Sites in Patients on Combined Pegylated Interferon and Ribavirin Therapy

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