Two PKR inhibitor HCV proteins correlate with early but not sustained response to interferon

Gerotto, Martina; Pero, Francesca Dal; Pontisso, Patrizia; Noventa, Franco; Gatta, Angelo; Alberti, Alfredo

doi:10.1053/gast.2000.20230

Cited by 59 publications

(43 citation statements)

References 28 publications

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“…In particular, PKR is targeted by the virus for inhibition, although other PKRindependent strategies may also be used (Francois et al 2000;Taylor 2001). The viral proteins NS5A and E2 have been shown to act as inhibitors of PKR function (Gerotto et al 2000;Taylor et al 2000;Pflugheber et al 2002), the former by binding to the kinase and preventing its dimerization ) and the latter by acting as a potential pseudo-substrate for the kinase (Taylor et al 1999Cochrane et al 2000). However, the roles of these proteins in determining the sensitivity of HCV to IFN treatment are controversial (Duverlie et al 1998;Odeberg et al 1998;Noguchi et al 2001;Sarrazin et al 2001;Tan and Katze 2001;Schiappa et al 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Because the IFN-induced antiviral response is a cell's first line of self-defence, for infection to progress, such defence must be overcome by the virus. Many viruses possess strategies for the down-regulation of IFN responses and of PKR activity in particular Korth and Katze 2000), and, in the case of HCV, the viral proteins NS5A and E2 have been shown to function as inhibitors of the protein kinase Pawlotsky and Germanidis 1999;Taylor et al 1999Taylor et al , 2001Cochrane et al 2000;Gerotto et al 2000;Pflugheber et al 2002).…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Introductionmentioning

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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“…15,16,[34][35][36][37][38] ‡According to references. [39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54] found between patients with and without HCC. When compared with the deduced consensus sequence derived from all sequenced isolates, 3 or more aa changes within the PKR-bd were observed in 60% of patients with HCC, but only in 6% of those without evidence of tumor.…”

Section: Discussionmentioning

confidence: 99%

High Amino Acid Variability Within the Ns5a of Hepatitis C Virus (Hcv) Is Associated With Hepatocellular Carcinoma in Patients With Hcv–1B-Related Cirrhosis

et al. 2001

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“…HCV genotype 1, particularly genotype 1b, are most resistant to combined IFN-R therapy [5] . Among viral factors, genetic variability has been studied in many regions of the HCV genome, mainly in hypervariable region 1 (HVR1) and PKR-eIF2α phosphorylation homology domain (PePHD) of E2 region and in PKRbd (including ISDR) of NS5A [17,22,[39][40][41][42][43] . However, few reports have studied the complete NS5A region [17,22] .…”

Section: Variability In Six Different Regions Along the Ns5a Genementioning

confidence: 99%

Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b during interferon or combined interferon-ribavirin therapy

Veillon

Payan²,

Guillou‐Guillemette³

et al. 2007

WJG

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AIM:To evaluate the implication of substitutions in the hepatitis C virus (HCV) non-structural 5A (NS5A) protein in the resistance of HCV during mono-interferon (IFN) or combined IFN-ribavirin (IFN-R) therapy. Although NS5A has been reported to interact with the HCV RNAdependent RNA polymerase, NS5B, as well as with many cellular proteins, the function of NS5A in the life cycle of HCV remains unclear.METHODS: HCV quasispecies were studied by cloning and sequencing of sequential isolates from patients infected by HCV genotype 1b. Patients were treated by IFN-α2b for 3 mo followed by IFN-α2b alone or combined IFN-R therapy for 9 additional months. Patients were categorized intro two groups based on their response to the treatments: 7 with sustained virological response (SVR) (quasispecies = 150) and 3 non-responders (NR) to IFN-R (quasispecies = 106). RESULTS:Prior to treatment, SVR patients displayed a lower complexity of quasispecies than NR patients. Most patients had a decrease in the complexity of quasispecies during therapy. Analysis of amino acids substitutions showed that the degree of the complexity of the interferon sensitivity-determining region (ISDR) and the V3 domain of NS5A protein was able to discriminate the two groups of patients. Moreover, SVR patients displayed more variability in the NS5A region than NR patients. CONCLUSION:These results suggest that detailed molecular analysis of the NS5A region may be important for understanding its function in IFN response during HCV 1b infection.

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Two PKR inhibitor HCV proteins correlate with early but not sustained response to interferon

Cited by 59 publications

References 28 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

High Amino Acid Variability Within the Ns5a of Hepatitis C Virus (Hcv) Is Associated With Hepatocellular Carcinoma in Patients With Hcv–1B-Related Cirrhosis

Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b during interferon or combined interferon-ribavirin therapy

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