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      Ribavirin: a drug active against many viruses with multiple effects on virus replication and propagation. Molecular basis of ribavirin resistance

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      Current Opinion in Virology

      Elsevier

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          Highlights

          • A broad spectrum antiviral effective against virtually all viruses tested in vitro.

          • Mechanism of action varies with virus and cell type.

          • Virus resistance often involves increase in replication fidelity.

          • Cell host resistance involves ribavirin uptake and metabolism.

          Abstract

          Ribavirin has proven to be effective against several viruses in the clinical setting and a multitude of viruses in vitro. With up to five different proposed mechanisms of action, recent advances have begun to discern the hierarchy of antiviral effects at play depending on the virus and the host conditions under scrutiny. Studies reveal that for many viruses, antiviral mechanisms may differ depending on cell type in vitro and in vivo. Further analyses are thus required to accurately identify mechanisms to more optimally determine clinical treatments. In recent years, a growing number of ribavirin resistant and sensitive variants have been identified. These variants not only inform on the specific mechanisms by which ribavirin enfeebles the virus, but also can themselves be tools to identify new antiviral compounds.

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          Most cited references 39

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          Determinants of RNA-dependent RNA polymerase (in)fidelity revealed by kinetic analysis of the polymerase encoded by a foot-and-mouth disease virus mutant with reduced sensitivity to ribavirin.

          A mutant poliovirus (PV) encoding a change in its polymerase (3Dpol) at a site remote from the catalytic center (G64S) confers reduced sensitivity to ribavirin and forms a restricted quasispecies, because G64S 3Dpol is a high-fidelity enzyme. A foot-and-mouth disease virus (FMDV) mutant that encodes a change in the polymerase catalytic site (M296I) exhibits reduced sensitivity to ribavirin without restricting the viral quasispecies. In order to resolve this apparent paradox, we have established a minimal kinetic mechanism for nucleotide addition by wild-type (WT) FMDV 3Dpol that permits a direct comparison to PV 3Dpol as well as to FMDV 3Dpol derivatives. Rate constants for correct nucleotide addition were on par with those of PV 3Dpol, but apparent binding constants for correct nucleotides were higher than those observed for PV 3Dpol. The A-to-G transition frequency was calculated to be 1/20,000, which is quite similar to that calculated for PV 3Dpol. The analysis of FMDV M296I 3Dpol revealed a decrease in the calculated ribavirin incorporation frequency (1/8,000) relative to that (1/4,000) observed for the WT enzyme. Unexpectedly, the A-to-G transition frequency was higher (1/8,000) than that observed for the WT enzyme. Therefore, FMDV selected a polymerase that increases the frequency of the misincorporation of natural nucleotides while specifically decreasing the frequency of the incorporation of ribavirin nucleotide. These studies provide a mechanistic framework for understanding FMDV 3Dpol structure-function relationships, provide the first direct analysis of the fidelity of FMDV 3Dpol in vitro, identify the beta9-alpha11 loop as a (in)fidelity determinant, and demonstrate that not all ribavirin-resistant mutants will encode high-fidelity polymerases.
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            Ribavirin and lethal mutagenesis of poliovirus: molecular mechanisms, resistance and biological implications.

            Positive strand RNA virus populations are a collection of similar but genetically different viruses. They exist as viral quasispecies due to the high mutation rates of the low fidelity viral RNA-dependent RNA polymerase (RdRp). It is thought that this genomic heterogeneity is advantageous to the population, allowing for adaptation to rapidly changing environments that present varying types and degrees of selective pressure. However, one consequence of this extensive diversity is the susceptibility to mutagens that further increase sequence variation. Since RNA viruses live at the edge of maximal variability, an increase in the mutation rate is likely to force the virus beyond the tolerable mutation frequency into 'error catastrophe'. One such mutagen, ribavirin, is an antiviral nucleoside analog that is mutagenic to several RNA viruses. Ribavirin is incorporated into the viral genome causing lethal mutagenesis and a subsequent decrease in the specific infectivity. Even so, passaging poliovirus in the presence of low to intermediate concentrations of the drug leads to the emergence of a viral population resistant to the effects of ribavirin. These viruses have a point mutation in the RdRp that increases the overall polymerase fidelity. Interestingly, as predicted by the quasispecies theory, ribavirin resistant viruses are less adaptable, as they are more susceptible to other non-mutagenic antiviral drugs and are highly attenuated in vivo. Here, we review the mechanism of action of ribavirin on poliovirus and other RNA viruses, the possibility for escape via increased fidelity of the viral polymerase, the consequences of this response on viral population dynamics, and the biological implications for the therapeutic use of mutagenic antiviral agents.
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              Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV-HIV International Panel.

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                Author and article information

                Contributors
                Journal
                Curr Opin Virol
                Curr Opin Virol
                Current Opinion in Virology
                Elsevier
                1879-6257
                1879-6265
                19 May 2014
                October 2014
                19 May 2014
                : 8
                : 10-15
                Affiliations
                Institut Pasteur, Viral Populations and Pathogenesis Unit, Centre National de la Recherche Scientifique UMR 3569, 28 rue du Dr Roux, Paris cedex 15, 75724, France
                Article
                S1879-6257(14)00093-5
                10.1016/j.coviro.2014.04.011
                7102760
                24846716
                Copyright © 2014 Elsevier B.V. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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