Genetic and biochemical diversity in the HCV NS5B RNA polymerase in the context of interferon α plus ribavirin therapy

[Guest guest]

http://www.ingentaconnect.com/content/bsc/jvh/2011/00000018/00000005/art00006

Journal of Viral Hepatitis, Volume 18, Number 5

Genetic and biochemical diversity in the HCV NS5B RNA polymerase in the context

of interferon α plus ribavirin therapy

Authors: Cao, F.1; Donlin, M. J.; , K.1; Cheng, X.1; Tavis, J. E.

Source: Journal of Viral Hepatitis, Volume 18, Number 5, May 2011 , pp.

349-357(9)

Publisher: Wiley-Blackwell

Abstract:

Summary. 

The hepatitis C virus (HCV) RNA polymerase (RdRp) may be a target of the drug

ribavirin, and it is an object of drug development. Independent isolates of any

HCV subtype differ genetically by approximately 10%, but the effects of this

variation on enzymatic activity and drug sensitivity are poorly understood. We

proposed that nucleotide use profiles (G/U ratio) among subtype 1b RdRps may

reflect their use of ribavirin. Here, we characterized how subtype 1b genetic

variation affects RNA polymerase activity and evaluated the G/U ratio as a

surrogate for ribavirin use during pegylated interferon α and ribavirin

therapy. Genetic and biochemical variation in the RdRp was compared between

responders who would be largely sensitive to ribavirin and relapsers who would

be mostly resistant. There were no consistent genetic differences between

responder and relapser RdRps. RNA polymerization, RNA binding and primer usage

varied widely among the RdRps, but these parameters did not differ significantly

between the response groups. The G/U ratio among a set of subtype 1a RdRps

increased rather than decreased following failed therapy, as would be expected

if it reflected ribavirin use. Finally, RdRp activity was significantly

associated with ALT levels. These data indicate that (i) current genetic

approaches cannot predict RNA polymerase behaviour, (ii) the G/U ratio is not a

surrogate for ribavirin use, (iii) RdRp activity may contribute to liver disease

by modulating viral mRNA and antigen levels, and (iv) drug candidates should be

tested against multiple patient-derived enzymes to ensure widespread efficacy

even within a viral subtype.

Document Type: Research article

DOI: 10.1111/j.1365-2893.2010.01316.x

Affiliations:1: Department of Molecular Microbiology and Immunology

Publication date: 2011-05-01

[Guest guest]

http://www.ingentaconnect.com/content/bsc/jvh/2011/00000018/00000005/art00006

Journal of Viral Hepatitis, Volume 18, Number 5

Genetic and biochemical diversity in the HCV NS5B RNA polymerase in the context

of interferon α plus ribavirin therapy

Authors: Cao, F.1; Donlin, M. J.; , K.1; Cheng, X.1; Tavis, J. E.

Source: Journal of Viral Hepatitis, Volume 18, Number 5, May 2011 , pp.

349-357(9)

Publisher: Wiley-Blackwell

Abstract:

Summary. 

The hepatitis C virus (HCV) RNA polymerase (RdRp) may be a target of the drug

ribavirin, and it is an object of drug development. Independent isolates of any

HCV subtype differ genetically by approximately 10%, but the effects of this

variation on enzymatic activity and drug sensitivity are poorly understood. We

proposed that nucleotide use profiles (G/U ratio) among subtype 1b RdRps may

reflect their use of ribavirin. Here, we characterized how subtype 1b genetic

variation affects RNA polymerase activity and evaluated the G/U ratio as a

surrogate for ribavirin use during pegylated interferon α and ribavirin

therapy. Genetic and biochemical variation in the RdRp was compared between

responders who would be largely sensitive to ribavirin and relapsers who would

be mostly resistant. There were no consistent genetic differences between

responder and relapser RdRps. RNA polymerization, RNA binding and primer usage

varied widely among the RdRps, but these parameters did not differ significantly

between the response groups. The G/U ratio among a set of subtype 1a RdRps

increased rather than decreased following failed therapy, as would be expected

if it reflected ribavirin use. Finally, RdRp activity was significantly

associated with ALT levels. These data indicate that (i) current genetic

approaches cannot predict RNA polymerase behaviour, (ii) the G/U ratio is not a

surrogate for ribavirin use, (iii) RdRp activity may contribute to liver disease

by modulating viral mRNA and antigen levels, and (iv) drug candidates should be

tested against multiple patient-derived enzymes to ensure widespread efficacy

even within a viral subtype.

Document Type: Research article

DOI: 10.1111/j.1365-2893.2010.01316.x

Affiliations:1: Department of Molecular Microbiology and Immunology

Publication date: 2011-05-01

[Guest guest]

http://www.ingentaconnect.com/content/bsc/jvh/2011/00000018/00000005/art00006

Journal of Viral Hepatitis, Volume 18, Number 5

Genetic and biochemical diversity in the HCV NS5B RNA polymerase in the context

of interferon α plus ribavirin therapy

Authors: Cao, F.1; Donlin, M. J.; , K.1; Cheng, X.1; Tavis, J. E.

Source: Journal of Viral Hepatitis, Volume 18, Number 5, May 2011 , pp.

349-357(9)

Publisher: Wiley-Blackwell

Abstract:

Summary. 

The hepatitis C virus (HCV) RNA polymerase (RdRp) may be a target of the drug

ribavirin, and it is an object of drug development. Independent isolates of any

HCV subtype differ genetically by approximately 10%, but the effects of this

variation on enzymatic activity and drug sensitivity are poorly understood. We

proposed that nucleotide use profiles (G/U ratio) among subtype 1b RdRps may

reflect their use of ribavirin. Here, we characterized how subtype 1b genetic

variation affects RNA polymerase activity and evaluated the G/U ratio as a

surrogate for ribavirin use during pegylated interferon α and ribavirin

therapy. Genetic and biochemical variation in the RdRp was compared between

responders who would be largely sensitive to ribavirin and relapsers who would

be mostly resistant. There were no consistent genetic differences between

responder and relapser RdRps. RNA polymerization, RNA binding and primer usage

varied widely among the RdRps, but these parameters did not differ significantly

between the response groups. The G/U ratio among a set of subtype 1a RdRps

increased rather than decreased following failed therapy, as would be expected

if it reflected ribavirin use. Finally, RdRp activity was significantly

associated with ALT levels. These data indicate that (i) current genetic

approaches cannot predict RNA polymerase behaviour, (ii) the G/U ratio is not a

surrogate for ribavirin use, (iii) RdRp activity may contribute to liver disease

by modulating viral mRNA and antigen levels, and (iv) drug candidates should be

tested against multiple patient-derived enzymes to ensure widespread efficacy

even within a viral subtype.

Document Type: Research article

DOI: 10.1111/j.1365-2893.2010.01316.x

Affiliations:1: Department of Molecular Microbiology and Immunology

Publication date: 2011-05-01

[Guest guest]

http://www.ingentaconnect.com/content/bsc/jvh/2011/00000018/00000005/art00006

Journal of Viral Hepatitis, Volume 18, Number 5

Genetic and biochemical diversity in the HCV NS5B RNA polymerase in the context

of interferon α plus ribavirin therapy

Authors: Cao, F.1; Donlin, M. J.; , K.1; Cheng, X.1; Tavis, J. E.

Source: Journal of Viral Hepatitis, Volume 18, Number 5, May 2011 , pp.

349-357(9)

Publisher: Wiley-Blackwell

Abstract:

Summary. 

The hepatitis C virus (HCV) RNA polymerase (RdRp) may be a target of the drug

ribavirin, and it is an object of drug development. Independent isolates of any

HCV subtype differ genetically by approximately 10%, but the effects of this

variation on enzymatic activity and drug sensitivity are poorly understood. We

proposed that nucleotide use profiles (G/U ratio) among subtype 1b RdRps may

reflect their use of ribavirin. Here, we characterized how subtype 1b genetic

variation affects RNA polymerase activity and evaluated the G/U ratio as a

surrogate for ribavirin use during pegylated interferon α and ribavirin

therapy. Genetic and biochemical variation in the RdRp was compared between

responders who would be largely sensitive to ribavirin and relapsers who would

be mostly resistant. There were no consistent genetic differences between

responder and relapser RdRps. RNA polymerization, RNA binding and primer usage

varied widely among the RdRps, but these parameters did not differ significantly

between the response groups. The G/U ratio among a set of subtype 1a RdRps

increased rather than decreased following failed therapy, as would be expected

if it reflected ribavirin use. Finally, RdRp activity was significantly

associated with ALT levels. These data indicate that (i) current genetic

approaches cannot predict RNA polymerase behaviour, (ii) the G/U ratio is not a

surrogate for ribavirin use, (iii) RdRp activity may contribute to liver disease

by modulating viral mRNA and antigen levels, and (iv) drug candidates should be

tested against multiple patient-derived enzymes to ensure widespread efficacy

even within a viral subtype.

Document Type: Research article

DOI: 10.1111/j.1365-2893.2010.01316.x

Affiliations:1: Department of Molecular Microbiology and Immunology

Publication date: 2011-05-01