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      Harnessing host–virus evolution in antiviral therapy and immunotherapy

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          Abstract

          Pathogen resistance and development costs are major challenges in current approaches to antiviral therapy. The high error rate of RNA synthesis and reverse‐transcription confers genome plasticity, enabling the remarkable adaptability of RNA viruses to antiviral intervention. However, this property is coupled to fundamental constraints including limits on the size of information available to manipulate complex hosts into supporting viral replication. Accordingly, RNA viruses employ various means to extract maximum utility from their informationally limited genomes that, correspondingly, may be leveraged for effective host‐oriented therapies. Host‐oriented approaches are becoming increasingly feasible because of increased availability of bioactive compounds and recent advances in immunotherapy and precision medicine, particularly genome editing, targeted delivery methods and RNAi. In turn, one driving force behind these innovations is the increasingly detailed understanding of evolutionarily diverse host–virus interactions, which is the key concern of an emerging field, neo‐virology. This review examines biotechnological solutions to disease and other sustainability issues of our time that leverage the properties of RNA and DNA viruses as developed through co‐evolution with their hosts.

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          Most cited references85

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          Asymmetry in the assembly of the RNAi enzyme complex.

          A key step in RNA interference (RNAi) is assembly of the RISC, the protein-siRNA complex that mediates target RNA cleavage. Here, we show that the two strands of an siRNA duplex are not equally eligible for assembly into RISC. Rather, both the absolute and relative stabilities of the base pairs at the 5' ends of the two siRNA strands determine the degree to which each strand participates in the RNAi pathway. siRNA duplexes can be functionally asymmetric, with only one of the two strands able to trigger RNAi. Asymmetry is the hallmark of a related class of small, single-stranded, noncoding RNAs, microRNAs (miRNAs). We suggest that single-stranded miRNAs are initially generated as siRNA-like duplexes whose structures predestine one strand to enter the RISC and the other strand to be destroyed. Thus, the common step of RISC assembly is an unexpected source of asymmetry for both siRNA function and miRNA biogenesis.
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            A defined commensal consortium elicits CD8 T cells and anti-cancer immunity

            There is a growing appreciation for the importance of the gut microbiota as a therapeutic target in various diseases. However, there are only a handful of known commensal strains that can potentially be used to manipulate host physiological functions. Here we isolate a consortium of 11 bacterial strains from healthy human donor faeces that is capable of robustly inducing interferon-γ-producing CD8 T cells in the intestine. These 11 strains act together to mediate the induction without causing inflammation in a manner that is dependent on CD103+ dendritic cells and major histocompatibility (MHC) class Ia molecules. Colonization of mice with the 11-strain mixture enhances both host resistance against Listeria monocytogenes infection and the therapeutic efficacy of immune checkpoint inhibitors in syngeneic tumour models. The 11 strains primarily represent rare, low-abundance components of the human microbiome, and thus have great potential as broadly effective biotherapeutics.
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              The 1.2-megabase genome sequence of Mimivirus.

              We recently reported the discovery and preliminary characterization of Mimivirus, the largest known virus, with a 400-nanometer particle size comparable to mycoplasma. Mimivirus is a double-stranded DNA virus growing in amoebae. We now present its 1,181,404-base pair genome sequence, consisting of 1262 putative open reading frames, 10% of which exhibit a similarity to proteins of known functions. In addition to exceptional genome size, Mimivirus exhibits many features that distinguish it from other nucleocytoplasmic large DNA viruses. The most unexpected is the presence of numerous genes encoding central protein-translation components, including four amino-acyl transfer RNA synthetases, peptide release factor 1, translation elongation factor EF-TU, and translation initiation factor 1. The genome also exhibits six tRNAs. Other notable features include the presence of both type I and type II topoisomerases, components of all DNA repair pathways, many polysaccharide synthesis enzymes, and one intein-containing gene. The size and complexity of the Mimivirus genome challenge the established frontier between viruses and parasitic cellular organisms. This new sequence data might help shed a new light on the origin of DNA viruses and their role in the early evolution of eukaryotes.
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                Author and article information

                Contributors
                steven.heaton@monash.edu
                Journal
                Clin Transl Immunology
                Clin Transl Immunology
                10.1002/(ISSN)2050-0068
                CTI2
                Clinical & Translational Immunology
                John Wiley and Sons Inc. (Hoboken )
                2050-0068
                08 July 2019
                2019
                : 8
                : 7 ( doiID: 10.1002/cti2.2019.8.issue-7 )
                : e1067
                Affiliations
                [ 1 ] Department of Biochemistry & Molecular Biology Monash University Clayton VIC Australia
                Author notes
                [*] [* ] Correspondence

                SM Heaton, Department of Biochemistry & Molecular Biology, Monash University, 23 Innovation Walk, Clayton, VIC 3800, Australia.

                E‐mail: steven.heaton@ 123456monash.edu

                Author information
                https://orcid.org/0000-0003-3323-8691
                Article
                CTI21067
                10.1002/cti2.1067
                6613463
                31312450
                8bc7843f-328c-446e-ba0b-f05f6b0efd14
                © 2019 The Author. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology Inc.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 30 April 2019
                : 07 June 2019
                : 09 June 2019
                Page count
                Figures: 2, Tables: 2, Pages: 17, Words: 11518
                Categories
                Special Feature Review
                Special Feature Reviews
                Custom metadata
                2.0
                cti21067
                2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.5 mode:remove_FC converted:08.07.2019

                All data generated or analysed during this study are included in this published article (and its supplementary information files).
                Immunology
                host-virus interaction,antiviral,host‐oriented,host–virus interaction,information economy paradox,interferon,multifunctional host protein,neo‐virology,rnai,vaccine
                All data generated or analysed during this study are included in this published article (and its supplementary information files).
                Immunology
                host-virus interaction, antiviral, host‐oriented, host–virus interaction, information economy paradox, interferon, multifunctional host protein, neo‐virology, rnai, vaccine

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