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      Nucleoside analogue 2’-C-methylcytidine inhibits hepatitis E virus replication but antagonizes ribavirin

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          Abstract

          Hepatitis E virus (HEV) infection has emerged as a global health issue, but no approved medication is available. The nucleoside analogue 2’-C-methylcytidine (2CMC), a viral polymerase inhibitor, has been shown to inhibit infection with a variety of viruses, including hepatitis C virus (HCV). Here, we report that 2CMC significantly inhibits the replication of HEV in a subgenomic replication model and in a system using a full-length infectious virus. Importantly, long-term treatment with 2CMC did not result in a loss of antiviral potency, indicating a high barrier to drug resistance development. However, the combination of 2CMC with ribavirin, an off-label treatment for HEV, exerts antagonistic effects. Our results indicate that 2CMC serves as a potential antiviral drug against HEV infection.

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          Adaptation of a genotype 3 hepatitis E virus to efficient growth in cell culture depends on an inserted human gene segment acquired by recombination.

          K Faulk, U Torian, Van-Anh Nguyen … (2012)
          An infectious cDNA clone of a genotype 3 strain of hepatitis E virus adapted to growth in HepG2/C3A human hepatoma cells was constructed. This virus was unusual in that the hypervariable region of the adapted virus contained a 171-nucleotide insertion that encoded 58 amino acids of human S17 ribosomal protein. Analyses of virus from six serial passages indicated that genomes with this insert, although initially rare, were selected during the first passage, suggesting it conferred a significant growth advantage. RNA transcripts from this cDNA and the viruses encoded by them were infectious for cells of both human and swine origin, the major host species for this zoonotic virus. Mutagenesis studies demonstrated that the S17 insert was a major factor in cell culture adaptation. Introduction of 54 synonymous mutations into the insert had no detectable effect, thus implicating protein, rather than RNA, as the important component. Truncation of the insert by 50% decreased the levels of successful transfection by ~3-fold. Substitution of the S17 sequence by a different ribosomal protein sequence or by GTPase-activating protein sequence resulted in a partial enhancement of transfection levels, whereas substitution with 58 amino acids of green fluorescent protein had no effect. Therefore, both the sequence length and the amino acid composition of the insert were important. The S17 sequence did not affect transfection of human hepatoma cells when inserted into the hypervariable region of a genotype 1 strain, but this chimeric genome acquired a dramatic ability to replicate in hamster cells.
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            The design of drugs for HIV and HCV.

            Erik De Clercq (2007)
            Since the discovery of the human immunodeficiency virus (HIV) in 1983, dramatic progress has been made in the development of novel antiviral drugs. The HIV epidemic fuelled the development of new antiviral drug classes, which are now combined to provide highly active antiretroviral therapies. The need for the treatment of hepatitis C virus (HCV), which was discovered in 1989, has also provided considerable impetus for the development of new classes of antiviral drugs, and future treatment strategies for chronic HCV might involve combination regimens that are analogous to those currently used for HIV. By considering the drug targets in the different stages of the life cycle of these two viruses, this article presents aspects of the history, medicinal chemistry and mechanisms of action of approved and investigational drugs for HIV and HCV, and highlights general lessons learned from anti-HIV-drug design that could be applied to HCV.
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              Hepatitis E Virus Infects Neurons and Brains.

              Bart C. Jacobs, Xinying Zhou, Fen Fen Huang … (2017)
              Hepatitis E virus (HEV), as a hepatotropic virus, is supposed to exclusively infect the liver and only cause hepatitis. However, a broad range of extrahepatic manifestations (in particular, idiopathic neurological disorders) have been recently reported in association with its infection. In this study, we have demonstrated that various human neural cell lines (embryonic stem cell-derived neural lineage cells) induced pluripotent stem cell-derived human neurons and primary mouse neurons are highly susceptible to HEV infection. Treatment with interferon-α or ribavirin, the off-label antiviral drugs for chronic hepatitis E, exerted potent antiviral activities against HEV infection in neural cells. More importantly, in mice and monkey peripherally inoculated with HEV particles, viral RNA and protein were detected in brain tissues. Finally, patients with HEV-associated neurological disorders shed the virus into cerebrospinal fluid, indicating a direct infection of their nervous system. Thus, HEV is neurotropic in vitro, and in mice, monkeys, and possibly humans. These results challenge the dogma of HEV as a pure hepatotropic virus and suggest that HEV infection should be considered in the differential diagnosis of idiopathic neurological disorders.
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                Author and article information

                Contributors
                Wenshi Wang: +31(0)107038695 , w.wang.2@erasmusmc.nl
                Journal
                Journal ID (nlm-ta): Arch Virol
                Journal ID (iso-abbrev): Arch. Virol
                Title: Archives of Virology
                Publisher: Springer Vienna (Vienna )
                ISSN (Print): 0304-8608
                ISSN (Electronic): 1432-8798
                Publication date (Electronic): 16 June 2017
                Publication date PMC-release: 16 June 2017
                Publication date (Print): 2017
                Volume: 162
                Issue: 10
                Pages: 2989-2996
                Affiliations
                ISNI 000000040459992X, GRID grid.5645.2, Department of Gastroenterology and Hepatology, , Erasmus MC-University Medical Center, ; Room Na-621 ‘s Gravendijkwal 230, NL-3015 CE Rotterdam, The Netherlands
                Article
                Publisher ID: 3444
                DOI: 10.1007/s00705-017-3444-8
                PMC ID: 5602043
                PubMed ID: 28623406
                SO-VID: bb4e803f-7386-4808-8836-f81fb44f27c2
                Copyright © © The Author(s) 2017
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Date received : 20 January 2017
                Date accepted : 3 June 2017
                Categories
                Subject: Original Article
                Custom metadata
                issue-copyright-statement © Springer-Verlag GmbH Austria 2017

                ScienceOpen disciplines: Microbiology & Virology
                Data availability:
                ScienceOpen disciplines: Microbiology & Virology

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