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Inosine triphosphat...
Inosine triphosphate pyrophosphatase dephosphorylates ribavirin triphosphate and reduced enzymatic activity potentiates mutagenesis in hepatitis C virus
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- Nyström, Kristina (author)
- Göteborgs universitet,University of Gothenburg
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- Wanrooij, Paulina H. (author)
- Umeå universitet,Institutionen för medicinsk kemi och biofysik
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- Waldenström, Jesper, 1985 (author)
- Göteborgs universitet,University of Gothenburg
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- Adamek, Ludmila (author)
- Göteborgs universitet,University of Gothenburg
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- Brunet, Sofia (author)
- Göteborgs universitet,University of Gothenburg
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- Said, Joanna (author)
- Göteborgs universitet,University of Gothenburg
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- Nilsson, Staffan, 1956 (author)
- Göteborgs universitet,University of Gothenburg,Chalmers tekniska högskola,Chalmers University of Technology
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Wind-Rotolo, Megan (author)
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- Hellstrand, Kristoffer, 1956 (author)
- Göteborgs universitet,University of Gothenburg
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- Norder, Helene (author)
- Göteborgs universitet,University of Gothenburg
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- Tang, Ka Wei (author)
- Göteborgs universitet,University of Gothenburg
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- Lagging, Martin, 1965 (author)
- Göteborgs universitet,University of Gothenburg
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(creator_code:org_t)
- American Society for Microbiology, 2018
- 2018
- English.
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In: Journal of Virology. - : American Society for Microbiology. - 0022-538X .- 1098-5514. ; 92:19
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Abstract
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- A third of humans carry genetic variants of the ITP pyrophosphatase (ITPase) gene (ITPA) that lead to reduced enzyme activity. Reduced ITPase activity was earlier reported to protect against ribavirin-induced hemolytic anemia and to diminish relapse following ribavirin and interferon therapy for hepatitis C virus (HCV) genotype 2 or 3 infections. While several hypotheses have been put forward to explain the antiviral actions of ribavirin, details regarding the mechanisms of interaction between reduced ITPase activity and ribavirin remain unclear. The in vitro effect of reduced ITPase activity was assessed by means of transfection of hepatocytes (Huh7.5 cells) with a small interfering RNA (siRNA) directed against ITPA or a negative-control siRNA in the presence or absence of ribavirin in an HCV culture system. Low ribavirin concentrations strikingly depleted intracellular GTP levels in HCV-infected hepatocytes whereas higher ribavirin concentrations induced G-to-A and C-to-U single nucleotide substitutions in the HCV genome, with an ensuing reduction of HCV RNA expression and HCV core antigen production. Ribavirin triphosphate (RTP) was dephosphorylated in vitro by recombinant ITPase to a similar extent as ITP, a naturally occurring substrate of ITPase, and reducing ITPA expression in Huh 7.5 cells by siRNA increased intracellular levels of RTP in addition to increasing HCV mutagenesis and reducing progeny virus production. Our results extend the understanding of the biological impact of reduced ITPase activity, demonstrate that RTP is a substrate of ITPase, and may point to personalized ribavirin dosage according to ITPA genotype in addition to novel antiviral strategies. IMPORTANCE This study highlights the multiple modes of action of ribavirin, including depletion of intracellular GTP and increased hepatitis C virus mutagenesis. In cell culture, reduced ITP pyrophosphatase (ITPase) enzyme activity affected the intracellular concentrations of ribavirin triphosphate (RTP) and augmented the impact of ribavirin on the mutation rate and virus production. Additionally, our results imply that RTP, similar to ITP, a naturally occurring substrate of ITPase, is dephosphorylated in vitro by ITPase.
Subject headings
- NATURVETENSKAP -- Biologi -- Mikrobiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Microbiology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Mikrobiologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Microbiology in the medical area (hsv//eng)
Keyword
- ITPA
- Ribavirin
- Mutagenesis
- ITPase
- Inosine triphosphate pyrophosphatase
- Mutagenesis
- ITP pyrophosphatase
- hepatitis C virus
Publication and Content Type
- art (subject category)
- ref (subject category)
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Nyström, Kristin ...
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Wanrooij, Paulin ...
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Waldenström, Jes ...
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Adamek, Ludmila
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Brunet, Sofia
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Said, Joanna
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Nilsson, Staffan ...
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Wind-Rotolo, Meg ...
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Hellstrand, Kris ...
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Norder, Helene
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Tang, Ka Wei
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Lagging, Martin, ...
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- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Microbiology
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Medical Biotechn ...
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and Medical Biotechn ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Microbiology in ...
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Journal of Virol ...
- By the university
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Chalmers University of Technology
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Umeå University