Evasive Maneuvers by Hepatitits C Virus

Lindenbach, Brett D.; Rice, Charles M.

doi:10.1002/hep.510380327

Cited by 15 publications

(17 citation statements)

References 24 publications

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“…Similar observations were demonstrated for the GSK benzothiadiazine polymerase inhibitors and HCV protease inhibitors (28,29,34,39,53,54). With all of the inhibitors studied, the levels of resistance caused by some of the single resistant mutants were greater than 100-fold above the wild-type IC 50 .…”

Section: Figsupporting

confidence: 76%

“…Two single NS3 mutations, A156V and D168V, were found in colonies selected by the combination of A-760759 and BILN-2061. Mutations A156T and D168A or D168V in HCV NS3 protease were previously observed in resistance studies using BILN-2061 alone (28,29,34). However, A156V is a new mutation first reported in the present study.…”

Section: A-782759-resistant Mutants Remained Susceptible To Other Clasupporting

confidence: 54%

“…Mutations A156T, D168A, and D168V in HCV NS3 protease have been previously observed in resistance selection studies using BILN-2061 alone (28,29,34), while mutation A156S has been reported to confer resistance to VX-950, but not to BILN-2061. However, A156V is a new mutation first reported in the present study.…”

Section: Figmentioning

confidence: 85%

“…Other mutations (H95Q, N411S, and Y448H) had IC 50 increases ranging from 28-to 44-fold (Table 3). We and others have previously reported that replicons containing mutations in the NS3 protease gene (A156T and D168A or D168V) confer high levels of resistance BILN-2061 (28,29,34).…”

Section: Methodsmentioning

confidence: 93%

“…Similarly, characterization of drug-resistant HCV replicons revealed that a single S282T mutation in NS5B polymerase conferred resistance to 2Ј-C Me-adenosine nucleosides (36). Furthermore, resistance to the NS3/4A serine protease inhibitors, including VX-950, BILN- 2061, and another acyclic tripeptide inhibitor, was also reported (28,29,34,54). Single amino acid substitutions (R155Q, A156S, A156T, D168V, D168A, and D168Y) in the NS3 protease gene mediated significant HCV replicon resistance to these compounds.…”

mentioning

confidence: 97%

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Mutations Conferring Resistance to a Hepatitis C Virus (HCV) RNA-Dependent RNA Polymerase Inhibitor Alone or in Combination with an HCV Serine Protease Inhibitor In Vitro

Pilot‐Matias

et al. 2005

Antimicrob Agents Chemother

121

112

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Compounds A-782759 (an N-1-aza-4-hydroxyquinolone benzothiadiazine) and BILN-2061 are specific antihepatitis C virus (HCV) agents that inhibit the RNA-dependent RNA polymerase and the NS3 serine protease, respectively. Both compounds display potent activity against HCV replicons in tissue culture. In order to characterize the development of resistance to these anti-HCV agents, HCV subgenomic 1b-N replicon cells were cultured with A-782759 alone or in combination with BILN-2061 at concentrations 10 times above their corresponding 50% inhibitory concentrations in the presence of neomycin. Single substitutions in the NS5B polymerase gene (H95Q, N411S, M414L, M414T, or Y448H) resulted in substantial decreases in susceptibility to A-782759. Similarly, replicons containing mutations in the NS5B polymerase gene (M414L or M414T), together with single mutations in the NS3 protease gene (A156V or D168V), conferred high levels of resistance to both A-782759 and BILN-2061. However, the A-782759-resistant mutants remained susceptible to nucleoside and two other classes of nonnucleoside NS5B polymerase inhibitors, as well as interferon. In addition, we found that the frequency of replicons resistant to both compounds was significantly lower than the frequency of resistance to the single compound. Furthermore, the dually resistant mutants displayed significantly reduced replication capacities compared to the wild-type replicon. These findings provide strategic guidance for the future treatment of HCV infection.Hepatitis C virus (HCV) is a leading cause of chronic liver disease, affecting over 4 million Americans and about 170 million people worldwide. The current standard of care for chronic HCV infection involves extended dosing with alpha interferon (IFN-␣) and ribavirin (10,14,18). However, these regimens have limited clinical benefit due to poor tolerability and limited efficacy (only approximately half of genotype 1 HCV-infected individuals have a sustained virological response, whereas the response rate improves significantly [ϳ80%] when genotypes 2 and 3 are treated) (9,11,35). Therefore, development of inhibitors against virally encoded targets is urgently needed.The HCV genome is a 9.6-kb single-stranded RNA of positive polarity encoding a large polyprotein, which is the precursor of at least 10 mature viral proteins: C, E1, E2, p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B (2). The HCV polymerase encoded by nonstructural protein 5B (NS5B) is responsible for HCV RNA-dependent RNA polymerase (RdRp) and terminal transferase activities (4,31,32). The N-terminal domain (approximately 180 amino acids) of NS3 and the small hydrophobic NS4A protein compose a heterodimeric enzyme catalyzing the posttranslational processing of the HCV NS proteins (1, 21). Both NS5B RdRp and NS3 serine protease are believed to be components of the HCV replication complex, responsible for viral RNA replication, and have been shown to be indispensable for HCV replication in chimpanzees (26).To date, a number of distinct classes of NS5B RdRp inhibitors...

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Section: Figsupporting

confidence: 76%

Section: A-782759-resistant Mutants Remained Susceptible To Other Clasupporting

confidence: 54%

Section: Figmentioning

confidence: 85%

Section: Methodsmentioning

confidence: 93%

mentioning

confidence: 97%

See 3 more Smart Citations

Mutations Conferring Resistance to a Hepatitis C Virus (HCV) RNA-Dependent RNA Polymerase Inhibitor Alone or in Combination with an HCV Serine Protease Inhibitor In Vitro

Pilot‐Matias

et al. 2005

Antimicrob Agents Chemother

121

112

View full text Add to dashboard Cite

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Perceived Quality of Care and Lifestyle Counseling Among Patients With Heart Disease

Jackson

Krishnan

Meccone

et al. 2010

Clinical Cardiology

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Background: To examine patients' perceived quality of care and reported receipt of information on diet and exercise related to cardiovascular disease prevention. Methods: Patients admitted with acute coronary syndromes or elective cardiac catheterization were eligible for enrollment. Baseline medical information was collected through medical-record review. Patients completed surveys at the time of hospitalization that included items on perceived quality of care and whether they had received information from a healthcare provider on diet and exercise as related to their heart. Perceived quality of care was grouped into 3 categories: (1) poor to fair, (2) good, and (3) very good to excellent. Results: Among the 182 cardiac patients who completed the survey, those who reported poor to fair quality of care were more likely to report that they had received no advice regarding diet as compared with those who perceived their quality of care as good or very good to excellent (61%, 59%, and 26%, respectively, P < 0.0001). A similar pattern was observed for exercise (71%, 74%, and 36%, respectively, P < 0.0001). Conclusions: Patients with low perceived quality of care were less likely to have discussed diet and exercise habits with healthcare providers. Improving receipt of lifestyle counseling is warranted given the central role that diet and exercise play in secondary prevention.

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Isatoribine, an Agonist of TLR7, Reduces Plasma Virus Concentration in Chronic Hepatitis C Infection *

et al. 2005

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Immune-based therapy is the mainstay treatment for chronic hepatitis C virus (HCV) infection but causes multiple side effects and achieves durable viral clearance in only approximately 50% of patients. Most new investigational anti-HCV compounds are direct-acting antivirals for which durability of response and risk of viral mutations and resistance are not yet known. Therefore, continuing discovery and development of new immune-based treatments is desirable. Toll-like receptors (TLRs) are pathogen recognition receptors that initiate the innate immune response. The responsiveness of HCV or other ongoing chronic systemic infections to treatment with a selective TLR agonist has not been reported. Isatoribine is a selective agonist of TLR7. In a proof-of-concept study, we found that once-daily 7-day treatment with intravenous isatoribine 800 mg caused a significant (P ‫؍‬ .001) reduction of plasma HCV RNA (mean, ؊0.76; range, ؊2.85 to ؉0.21 log 10 units) in otherwise untreated patients (n ‫؍‬ 12) who were chronically infected with HCV. Viral load reduction occurred in patients infected with genotype 1 as well as non-genotype 1 HCV. The reduction of viral load was correlated with induction of markers of a heightened immune antiviral state, including 2-, 5-oligoadenylate synthetase levels in whole blood. This treatment was well tolerated, with a low frequency of mild to moderate adverse events. In conclusion, systemic administration of the selective TLR7 agonist isatoribine resulted in dose-dependent changes in immunologic biomarkers and a statistically significant antiviral effect with relatively few and mild side effects. ( C hronic infection with hepatitis C virus (HCV) is a major cause of morbidity and mortality, affecting 170 million persons worldwide. 1,2 Although chronic HCV infection is largely asymptomatic, persistent infection over many years significantly increases the risk of cirrhosis, hepatocellular carcinoma, and end-stage liver disease. [1][2][3][4] The current standard-of-care treatment for HCV infection is immune based, consisting of an injectable interferon-alpha product (a type 1 cytokine) in combination with the orally administered nucleoside analog ribavirin. 1,5,6 This treatment can durably clear HCV from approximately 50% of treated patients but has multiple side effects that often result in early abandonment of treatment. Thus, a need remains for novel anti-HCV therapies to improve response rates and reduce adverse effects.A variety of investigational anti-HCV compounds are approaching or undergoing clinical studies. 7 Aside from modified versions of interferon-alpha and ribavirin, most investigational compounds are direct-acting antivirals that bind to virally encoded targets. Whether durable virological responses can be achieved with direct-acting anti-HCV agents is unknown. Moreover, the high rate and low fidelity of HCV replication may lead to rapid emergence of resistance to direct-acting antivirals. 8,9 In light of these uncertainties, continuing to explore immune stimulation as an appro...

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Evasive Maneuvers by Hepatitits C Virus

Cited by 15 publications

References 24 publications

Mutations Conferring Resistance to a Hepatitis C Virus (HCV) RNA-Dependent RNA Polymerase Inhibitor Alone or in Combination with an HCV Serine Protease Inhibitor In Vitro

Mutations Conferring Resistance to a Hepatitis C Virus (HCV) RNA-Dependent RNA Polymerase Inhibitor Alone or in Combination with an HCV Serine Protease Inhibitor In Vitro

Perceived Quality of Care and Lifestyle Counseling Among Patients With Heart Disease

Isatoribine, an Agonist of TLR7, Reduces Plasma Virus Concentration in Chronic Hepatitis C Infection *

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