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Inosine Triphosphate Pyrophosphatase Dephosphorylates Ribavirin Triphosphate and Reduced Enzymatic Activity Potentiates Mutagenesis in Hepatitis C Virus

Journal article
Authors Kristina Nyström
P. H. Wanrooij
Jesper Waldenström
Ludmila Adamek
Sofia Brunet
Joanna Said
Staffan Nilsson
M. Wind-Rotolo
Kristoffer Hellstrand
Helene Norder
Ka-Wei Tang
Martin Lagging
Published in Journal of Virology
Volume 92
Issue 19
ISSN 0022-538X
Publication year 2018
Published at Department of Mathematical Sciences
Wallenberg Laboratory
Institute of Biomedicine, Department of Pathology
Institute of Biomedicine, Department of Infectious Medicine
Language en
Links dx.doi.org/10.1128/jvi.01087-18
Keywords hepatitis C virus, ITPA, ITP pyrophosphatase, ITPase, ribavirin, mutagenesis, inosine triphosphate, real-time pcr, pyrophosphohydrolase deficiency, treatment response, antiviral activity, mycophenolic-acid, gene-expression, infection, interferon, therapy, population
Subject categories Microbiology in the medical area

Abstract

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.

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