The Protein Kinase–Interacting Domain in the Hepatitis C Virus Envelope Glycoprotein–2 Gene Is Highly Conserved in Genotype 1–Infected Patients Treated with Interferon

Polyak, Stephen J.; Nousbaum, Jean-Baptiste; Larson, Anne M.; Cotler, Scott J.; Carithers, Robert L.; Gretch, David R.

doi:10.1086/315720

Cited by 35 publications

(22 citation statements)

References 34 publications

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“…This similarity was greater for HCV genotype 1 than genotype 2 or 3. However, these findings have not been supported in other studies [27,28], indicating that PePHD is not a reliable marker of IFN resistance.…”

Section: Hcv Genetic Heterogeneity and Ifn/rbv Resistancecontrasting

confidence: 59%

Epistatic connectivity among HCV genomic sites as a genetic marker of interferon resistance

Lara¹,

Khudyakov²

2012

Antivir Ther

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The current standard-of-care therapy of patients with hepatitis C virus (HCV) infection involves treatment with interferon (IFN) and ribavirin. Host demographic and genetic factors as well as HCV genetic heterogeneity were shown to be associated with outcomes of therapy. Although resistance to IFN/RBV remains to be an important clinical and public health problem, there are no reliable genetic markers for the prediction of the therapy outcomes. Recently, it was shown that adaptation to IFN, a major constituent of the host innate immunity, is reflected in the HCV genetic composition and epistatic connectivity among polymorphic genomic sites, thus providing novel genetic markers of IFN resistance. Consideration of coordinated evolution among HCV genomic sites allows for the identification of these genetic markers from short regions of the HCV genome and accurate prediction of the therapy outcomes. The HCV genomic coevolution offers a general framework for the detection of predisposition to IFN resistance, and to resistance to direct-acting antivirals when they become introduced.

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Section: Hcv Genetic Heterogeneity and Ifn/rbv Resistancecontrasting

confidence: 59%

Epistatic connectivity among HCV genomic sites as a genetic marker of interferon resistance

Lara¹,

Khudyakov²

2012

Antivir Ther

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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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“…Both the NS5A and E2 proteins inhibit PKR activity, which is postulated to allow HCV replication to continue in the presence of an IFN-induced antiviral response (19,77). For E2, the interaction with PKR requires a 12-amino-acid domain (77), which is a highly stable element that does not mutate during antiviral therapy (1,57). For NS5A, the interaction with PKR requires the IFN-sensitivity-determining region (ISDR) on NS5A, a region that is associated with clinical IFN resistance in Japanese and Spanish patients (6,12,13,36,67).…”

Section: Hepatitis C Virus (Hcv) a Major Cause Of Liver Disease Worlmentioning

confidence: 99%

Hepatitis C Virus Nonstructural 5A Protein Induces Interleukin-8, Leading to Partial Inhibition of the Interferon-Induced Antiviral Response

Polyak

Khabar

Paschal

et al. 2001

J Virol

291

213

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Hepatitis C virus (HCV), a major cause of liver disease worldwide, is frequently resistant to the antiviral alpha interferon (IFN). The HCV nonstructural 5A (NS5A) protein has been implicated in HCV antiviral resistance in many studies. NS5A antagonizes the IFN antiviral response in vitro, and one mechanism is via inhibition of a key IFN-induced enzyme, the double-stranded-RNA-activated protein kinase (PKR). In the present study we determined if NS5A uses other strategies to subvert the IFN system. Expression of full-length NS5A proteins from patients who exhibited a complete response (FL-NS5A-CR) or were nonresponsive (FL-NS5A-NR) to IFN therapy in HeLa cells had no effect Alpha interferon (IFN) is a Food and Drug Administrationapproved treatment for chronic HCV infection. Only 8 to 12% of patients with HCV genotype 1 have a sustained clinical virological response to IFN therapy (4,43,61). Recently, combination therapy with interferon and the guanosine analogue ribavirin was shown to be superior to IFN monotherapy in producing sustained biochemical and virological responses (9,45,62). However, despite the significant improvement in rates of sustained response, as many as 60% of patients with hightiter HCV genotype 1 infection are nonresponsive to combination therapy.When IFN binds to its receptor, two receptor-associated tyrosine kinases of the STAT/JAK family, Tyk2 and Jak1, become activated. These activated kinases phosphorylate STAT-1 and STAT-2 on a single conserved tyrosine residue (8). STAT-1 and STAT-2 form heterodimers and combine with the p48 protein to form an active transcription factor known as IFN-stimulated gene factor 3 (ISGF-3). ISGF-3 binds to a common element termed the interferon-stimulated response element (ISRE), found in the promoter regions of all IFNstimulated genes, whereupon transcription occurs. Expression of the entire HCV polyprotein has been shown to inhibit IFNinduced STAT/JAK signaling in human U2-OS osteosarcoma cells (25). It was not reported which HCV protein was responsible for this effect.Recent studies have led to exciting discoveries in the emerging research area of the roles of HCV proteins in antiviral resistance. Two examples are the interaction of the HCV non-* Corresponding author. Mailing address:

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The Protein Kinase–Interacting Domain in the Hepatitis C Virus Envelope Glycoprotein–2 Gene Is Highly Conserved in Genotype 1–Infected Patients Treated with Interferon

Cited by 35 publications

References 34 publications

Epistatic connectivity among HCV genomic sites as a genetic marker of interferon resistance

Epistatic connectivity among HCV genomic sites as a genetic marker of interferon resistance

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

Hepatitis C Virus Nonstructural 5A Protein Induces Interleukin-8, Leading to Partial Inhibition of the Interferon-Induced Antiviral Response

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