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

Nyström, Kristina; Wanrooij, Paulina H.; Waldenström, J; Adamek, Ludmila; Brunet, Sofia; Said, Joanna; Nilsson, Staffan; Wind‐Rotolo, Megan; Hellstrand, Kristoffer; Nordér, Helené; Tang, Ka-Wei; Lagging, Martin

doi:10.1128/jvi.01087-18

Cited by 19 publications

(20 citation statements)

References 63 publications

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“…Phenotypes of mammalian ITPase mutants can be severe, with ITPase-deficient mice showing growth retardation and premature death (Sakumi et al, 2010). In humans, many drug interactions can be affected by ITPA deficiency, particularly in the use of purine analogs and the antiviral nucleotide triphosphate ribavirin (Nyström et al, 2018). ITP concentration has been shown to increase in humans under disease conditions following deamination of ATP.…”

Section: The Imp Ortan Ce Of Itpa S E In Deple Ti On Of Mutag Enic P Ool S Of Non C Anonic Al Nucleotide Smentioning

confidence: 99%

Viral inosine triphosphatase: A mysterious enzyme with typical activity, but an atypical function

James

Seal

Bailey

et al. 2021

Molecular Plant Pathology

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Plant viruses typically have highly condensed genomes, yet the plant‐pathogenic viruses Cassava brown streak virus, Ugandan cassava brown streak virus, and Euphorbia ringspot virus are unusual in encoding an enzyme not yet found in any other virus, the “house‐cleaning” enzyme inosine triphosphatase. Inosine triphosphatases (ITPases) are highly conserved enzymes that occur in all kingdoms of life and perform a house‐cleaning function by hydrolysing the noncanonical nucleotide inosine triphosphate to inosine monophosphate. The ITPases encoded by cassava brown streak virus and Ugandan cassava brown streak virus have been characterized biochemically and are shown to have typical ITPase activity. However, their biological role in virus infection has yet to be elucidated. Here we review what is known of viral‐encoded ITPases and speculate on potential roles in infection with the aim of generating a greater understanding of cassava brown streak viruses, a group of the world's most devastating viruses.

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Section: The Imp Ortan Ce Of Itpa S E In Deple Ti On Of Mutag Enic P Ool S Of Non C Anonic Al Nucleotide Smentioning

confidence: 99%

Viral inosine triphosphatase: A mysterious enzyme with typical activity, but an atypical function

James

Seal

Bailey

et al. 2021

Molecular Plant Pathology

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“…Prior to initiating the present study, we hypothesized that among patients lacking IFN-k4, reduced ITPase activity might be additionally beneficial based on prior studies [8,9]. Indeed, a highly significant association to this effect was noted among male patients lacking IFN-k4 (TT rs368234815 homozygous), where reduced ITPase activity improved the likelihood to spontaneously resolve to 65%, as compared to 30% in those with full enzymatic activity.…”

Section: Discussionmentioning

confidence: 95%

“…ITPase is an enzyme that metabolizes non-canonical triphosphate nucleotides (e.g., XTP and ITP, Figure 4), which otherwise might be incorporated in host or viral genomes. Additionally, ribavirin triphosphate (RTP) is dephosphorylated by ITPase in vitro to ribavirin monophosphate (RMP) at a comparable rate to ITP [9]. Inosine containing single-stranded RNA is highly immunogenic and could theoretically cause a better immune response [22,23].…”

Section: Discussionmentioning

confidence: 99%

“…Reduced ITPase activity, present in approximately one third of HCV infected patients, was significantly associated with increased treatment efficacy mediated by reduced relapse risk following interferon-based therapy for HCV genotype 2/3 [8]. Furthermore, among HCV genotype 1 or 3 infected patients with baseline NS5A resistanceassociated substitutions (RASs), reduced ITPase activity improved outcome following some direct acting anti-viral (DAA) regimens [9] secondary to a ribavirin-like reduced relapse risk.…”

Section: Introductionmentioning

confidence: 99%

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Absence of interferon-λ 4 enhances spontaneous clearance of acute hepatitis C virus genotypes 1-3 infection

Waldenström

Kåberg

Blomé

et al. 2021

Scandinavian Journal of Gastroenterology

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Objectives: Absence of a functional interferon-k 4 (IFN-k4) gene (IFNL4) predicts spontaneous resolution of acute hepatitis C virus (HCV) infections in regions with a predominance of genotype 1, whereas variants of the inosine triphosphate pyrophosphatase (ITPase) gene (ITPA) entailing reduced activity associate with increased sustained virologic response rates following some therapeutic regimens. This study aimed at investigating the impact of IFNL4 on acute HCV genotype 2 or 3 infections, and whether ITPase activity influenced outcome. Materials and Methods: Two hundred and seven people who injected drugs (PWID) with documented anti-HCV seroconversion, and 57 PWID with reinfection with HCV were analyzed regarding IFNL4 (rs368234815 and rs12979860) and ITPA (rs1127354 and rs7270101), and longitudinally followed regarding HCV RNA. Results: The spontaneous clearance of HCV infection in anti-HCV seronegative PWID was enhanced when IFN-k4 was absent (44% vs. 20% for IFNL4 TT/TT rs1368234815 and DG rs1368234815 respectively, p < .001; OR 3.2) across genotypes 1-3. The proportion lacking IFN-k4 was further increased following resolution of repeated re-exposure to HCV (74% among re-infected participants who had cleared at least two documented HCV infections). ITPA genetic variants did not independently impact on the outcome, but among males lacking IFN-k4, reduced ITPase activity markedly augmented the likelihood of resolution (65% vs. 29% for <100% and 100% ITPase activity, p ¼ .006). Conclusions: Absence of IFN-k4 entails an enhanced likelihood of spontaneous resolution both following primary acute infection and repeated re-exposure to HCV across genotypes 1-3. Among men lacking IFN-k4, reduced ITPase activity improved outcome.

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“…Favipiravir and ribavirin exerted a synergistic activity against Rift Valley fever virus and viral hemorrhagic fever viruses in animal models (46,61,62). Synergism between favipiravir and ribavirin may result from their independent mechanisms of activity (10,(63)(64)(65)(66), and a role of lethal mutagenesis in the reinforcement of their effectiveness has not been established.…”

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confidence: 99%

Synergistic Lethal Mutagenesis of Hepatitis C Virus

Gallego

Soria

Gregori

et al. 2019

Antimicrob Agents Chemother

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Lethal mutagenesis is an antiviral approach that consists of extinguishing a virus by an excess of mutations acquired during replication in the presence of a mutagenic agent, often a nucleotide analogue. One of its advantages is its broad-spectrum nature, which renders the strategy potentially effective against emergent RNA viral infections. Here we describe the synergistic lethal mutagenesis of hepatitis C virus (HCV) by a combination of favipiravir (T-705) and ribavirin. Synergy has been documented over a broad range of analogue concentrations using the Chou-Talalay method implemented in CompuSyn graphics software, with the average dose reduction index (DRI) being above 1 (68.02 ± 101.6 for favipiravir and 5.83 ± 6.07 for ribavirin) and the average combination indices (CI) being below 1 (0.52 ± 0.28). Furthermore, analogue concentrations that individually did not extinguish high-fitness HCV in 10 serial infections extinguished high-fitness HCV in 1 to 2 passages when used in combination. Although both analogues displayed a preference for G → A and C → U transitions, deep sequencing analysis of mutant spectra indicated a different preference of the two analogues for the mutation sites, thus unveiling a new possible synergy mechanism in lethal mutagenesis. The prospects for synergy among mutagenic nucleotides as a strategy to confront emerging viral infections are discussed.

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

Cited by 19 publications

References 63 publications

Viral inosine triphosphatase: A mysterious enzyme with typical activity, but an atypical function

Viral inosine triphosphatase: A mysterious enzyme with typical activity, but an atypical function

Absence of interferon-λ 4 enhances spontaneous clearance of acute hepatitis C virus genotypes 1-3 infection

Synergistic Lethal Mutagenesis of Hepatitis C Virus

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