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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Harnessing host–virus evolution in antiviral therapy and immunotherapy</title><author><name sortKey="Heaton, Steven M" sort="Heaton, Steven M" uniqKey="Heaton S" first="Steven M" last="Heaton">Steven M. Heaton</name><affiliation><nlm:aff id="cti21067-aff-0001"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31312450</idno><idno type="pmc">6613463</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613463</idno><idno type="RBID">PMC:6613463</idno><idno type="doi">10.1002/cti2.1067</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000892</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000892</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Harnessing host–virus evolution in antiviral therapy and immunotherapy</title><author><name sortKey="Heaton, Steven M" sort="Heaton, Steven M" uniqKey="Heaton S" first="Steven M" last="Heaton">Steven M. Heaton</name><affiliation><nlm:aff id="cti21067-aff-0001"></nlm:aff></affiliation></author></analytic><series><title level="j">Clinical & Translational Immunology</title><idno type="eISSN">2050-0068</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Abstract</title><p>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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Patel, T" uniqKey="Patel T">T Patel</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="review-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Clin Transl Immunology</journal-id><journal-id journal-id-type="iso-abbrev">Clin Transl Immunology</journal-id><journal-id journal-id-type="doi">10.1002/(ISSN)2050-0068</journal-id><journal-id journal-id-type="publisher-id">CTI2</journal-id><journal-title-group><journal-title>Clinical & Translational Immunology</journal-title></journal-title-group><issn pub-type="epub">2050-0068</issn><publisher><publisher-name>John Wiley and Sons Inc.</publisher-name><publisher-loc>Hoboken</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31312450</article-id><article-id pub-id-type="pmc">6613463</article-id><article-id pub-id-type="doi">10.1002/cti2.1067</article-id><article-id pub-id-type="publisher-id">CTI21067</article-id><article-categories><subj-group subj-group-type="overline"><subject>Special Feature Review</subject></subj-group><subj-group subj-group-type="heading"><subject>Special Feature Reviews</subject></subj-group></article-categories><title-group><article-title>Harnessing host–virus evolution in antiviral therapy and immunotherapy</article-title><alt-title alt-title-type="left-running-head">SM Heaton</alt-title></title-group><contrib-group><contrib id="cti21067-cr-0001" contrib-type="author" corresp="yes"><name><surname>Heaton</surname><given-names>Steven M</given-names></name><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0003-3323-8691</contrib-id><xref ref-type="aff" rid="cti21067-aff-0001"><sup>1</sup></xref><address><email>steven.heaton@monash.edu</email></address></contrib></contrib-group><aff id="cti21067-aff-0001"><label><sup>1</sup></label><named-content content-type="organisation-division">Department of Biochemistry & Molecular Biology</named-content><institution>Monash University</institution><city>Clayton</city><named-content content-type="country-part">VIC</named-content><country country="AU">Australia</country></aff><author-notes><corresp id="correspondenceTo"><label>*</label><bold>Correspondence</bold><break></break>SM Heaton, Department of Biochemistry & Molecular Biology, Monash University, 23 Innovation Walk, Clayton, VIC 3800, Australia.<break></break>E‐mail: <email>steven.heaton@monash.edu</email><break></break></corresp></author-notes><pub-date pub-type="epub"><day>08</day><month>7</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>8</volume><issue>7</issue><issue-id pub-id-type="doi">10.1002/cti2.2019.8.issue-7</issue-id><elocation-id>e1067</elocation-id><history><date date-type="received"><day>30</day><month>4</month><year>2019</year></date><date date-type="rev-recd"><day>07</day><month>6</month><year>2019</year></date><date date-type="accepted"><day>09</day><month>6</month><year>2019</year></date></history><permissions><pmc-comment> © 2019 Australian and New Zealand Society for Immunology Inc. </pmc-comment>
<copyright-statement content-type="article-copyright">© 2019 The Author. <italic>Clinical & Translational Immunology</italic> published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology Inc.</copyright-statement><license license-type="creativeCommonsBy"><license-p>This is an open access article under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link> License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="file:CTI2-8-e1067.pdf"></self-uri><abstract id="cti21067-abs-0001"><title>Abstract</title><p>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.</p></abstract><abstract abstract-type="graphical" id="cti21067-abs-0002"><p>Virus‐oriented therapeutics are often limited by playing into the evolutionary strengths of viruses. These same ‘strengths’ impose an information economy paradox upon RNA viruses, which can be resolved by subverting multifunctional host proteins. Current and future technologies may leverage such ‘strengths’ of viral evolution, enabling viable host‐oriented therapeutics that solve disease and sustainability issues of our time.<boxed-text position="anchor" content-type="graphic" id="cti21067-blkfxd-0001" orientation="portrait"><graphic xlink:href="CTI2-8-e1067-g003.jpg" position="anchor" id="nlm-graphic-1" orientation="portrait"></graphic></boxed-text></p></abstract><kwd-group kwd-group-type="author-generated"><kwd id="cti21067-kwd-0001">antiviral</kwd><kwd id="cti21067-kwd-0002">host‐oriented</kwd><kwd id="cti21067-kwd-0003">host–virus interaction</kwd><kwd id="cti21067-kwd-0004">information economy paradox</kwd><kwd id="cti21067-kwd-0005">interferon</kwd><kwd id="cti21067-kwd-0006">multifunctional host protein</kwd><kwd id="cti21067-kwd-0007">neo‐virology</kwd><kwd id="cti21067-kwd-0008">RNAi</kwd><kwd id="cti21067-kwd-0009">vaccine</kwd></kwd-group><counts><fig-count count="2"></fig-count><table-count count="2"></table-count><page-count count="17"></page-count><word-count count="11518"></word-count></counts><custom-meta-group><custom-meta><meta-name>source-schema-version-number</meta-name><meta-value>2.0</meta-value></custom-meta><custom-meta><meta-name>cover-date</meta-name><meta-value>2019</meta-value></custom-meta><custom-meta><meta-name>details-of-publishers-convertor</meta-name><meta-value>Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.0 mode:remove_FC converted:16.04.2020</meta-value></custom-meta></custom-meta-group></article-meta></front><body id="cti21067-body-0001"><sec id="cti21067-sec-0001"><title>Introduction</title><p>Most human‐infective viruses are RNA viruses, 94% of which harbour a single‐stranded RNA (ssRNA) genome.<xref rid="cti21067-bib-0001" ref-type="ref">1</xref> These include established pathogens such as HIV and dengue virus (DenV), most high‐profile emerging pathogens this decade [e.g. Zika virus (ZikV), SARS‐coronavirus (SARS‐CoV) and avian influenza], re‐emerging pathogens including measles virus (MV) and every pathogen prioritised in the recent WHO R&D Blueprint.<xref rid="cti21067-bib-0002" ref-type="ref">2</xref> Furthermore, climate change‐related factors are likely to drive changes in future dispersion or transmission of viruses including mosquito‐borne viruses such as DenV and ZikV.<xref rid="cti21067-bib-0003" ref-type="ref">3</xref> The disease burden associated with many of the 214 human‐infective RNA virus species is large and growing, yet only five have US Food and Drug Administration (FDA)‐approved antivirals available and nearly all target virus proteins (Table <xref rid="cti21067-tbl-0001" ref-type="table">1</xref>).</p><table-wrap id="cti21067-tbl-0001" xml:lang="en" orientation="portrait" position="float"><label>Table 1</label><caption><p>Types and targets of current Food and Drug Administration‐approved antiviral drugs</p></caption><table frame="hsides" rules="groups"><col style="border-right:solid 1px #000000" span="1"></col><col style="border-right:solid 1px #000000" span="1"></col><col style="border-right:solid 1px #000000" span="1"></col><col style="border-right:solid 1px #000000" span="1"></col><col style="border-right:solid 1px #000000" span="1"></col><thead valign="top"><tr style="border-bottom:solid 1px #000000"><th align="left" valign="top" rowspan="1" colspan="1">Name</th><th align="center" valign="top" rowspan="1" colspan="1">Type</th><th align="center" valign="top" rowspan="1" colspan="1">Approved</th><th align="center" valign="top" rowspan="1" colspan="1">Target</th><th align="center" valign="top" rowspan="1" colspan="1">Virus/es</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Cytarabine</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1969</td><td align="left" rowspan="1" colspan="1">Host</td><td align="left" rowspan="1" colspan="1">HSV</td></tr><tr><td align="left" rowspan="1" colspan="1">Interferon alfa‐2b</td><td align="left" rowspan="1" colspan="1">Protein</td><td align="left" rowspan="1" colspan="1">1997</td><td align="left" rowspan="1" colspan="1">Host</td><td align="left" rowspan="1" colspan="1">HBV, HCV</td></tr><tr><td align="left" rowspan="1" colspan="1">Interferon alfacon‐1</td><td align="left" rowspan="1" colspan="1">Protein</td><td align="left" rowspan="1" colspan="1">1997</td><td align="left" rowspan="1" colspan="1">Host</td><td align="left" rowspan="1" colspan="1">HCV</td></tr><tr><td align="left" rowspan="1" colspan="1">Peginterferon alfa‐2b</td><td align="left" rowspan="1" colspan="1">Protein</td><td align="left" rowspan="1" colspan="1">2001</td><td align="left" rowspan="1" colspan="1">Host</td><td align="left" rowspan="1" colspan="1">HCV</td></tr><tr><td align="left" rowspan="1" colspan="1">Peginterferon alfa‐2a</td><td align="left" rowspan="1" colspan="1">Protein</td><td align="left" rowspan="1" colspan="1">2002</td><td align="left" rowspan="1" colspan="1">Host</td><td align="left" rowspan="1" colspan="1">HBV, HCV</td></tr><tr><td align="left" rowspan="1" colspan="1">Ribavirin</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2002</td><td align="left" rowspan="1" colspan="1">Host</td><td align="left" rowspan="1" colspan="1">HCV</td></tr><tr><td align="left" rowspan="1" colspan="1">Enfuvirtide</td><td align="left" rowspan="1" colspan="1">Peptide</td><td align="left" rowspan="1" colspan="1">2003</td><td align="left" rowspan="1" colspan="1">Host</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Maraviroc</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2007</td><td align="left" rowspan="1" colspan="1">Host</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Idoxuridine</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1963</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HSV</td></tr><tr><td align="left" rowspan="1" colspan="1">Amantadine</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1966</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">IAV</td></tr><tr><td align="left" rowspan="1" colspan="1">Vidarabine</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1976</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HSV, VZV</td></tr><tr><td align="left" rowspan="1" colspan="1">Zidovudine</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1987</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Ganciclovir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1989</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">CMV</td></tr><tr><td align="left" rowspan="1" colspan="1">Foscarnet</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1991</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HSV</td></tr><tr><td align="left" rowspan="1" colspan="1">Zalcitabine</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1992</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Stavudine</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1994</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Rimantadine</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1994</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">IAV</td></tr><tr><td align="left" rowspan="1" colspan="1">Saquinavir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1995</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Lamivudine</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1995</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV, HBV</td></tr><tr><td align="left" rowspan="1" colspan="1">Trifluridine</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1995</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HSV</td></tr><tr><td align="left" rowspan="1" colspan="1">Valaciclovir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1995</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HSV, VZV</td></tr><tr><td align="left" rowspan="1" colspan="1">Cidofovir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1996</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">CMV</td></tr><tr><td align="left" rowspan="1" colspan="1">Didanosine</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1996</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Indinavir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1996</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Nevirapine</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1996</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Ritonavir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1996</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Penciclovir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1996</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HSV</td></tr><tr><td align="left" rowspan="1" colspan="1">RespiGam</td><td align="left" rowspan="1" colspan="1">Plasma antibody</td><td align="left" rowspan="1" colspan="1">1996</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">RSV</td></tr><tr><td align="left" rowspan="1" colspan="1">Delavirdine</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1997</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Nelfinavir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1997</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Famciclovir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1997</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HSV</td></tr><tr><td align="left" rowspan="1" colspan="1">Acyclovir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1997</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HSV, VZV</td></tr><tr><td align="left" rowspan="1" colspan="1">Fomivirsen</td><td align="left" rowspan="1" colspan="1">Oligonucleotide</td><td align="left" rowspan="1" colspan="1">1998</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">CMV</td></tr><tr><td align="left" rowspan="1" colspan="1">Abacavir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1998</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Efavirenz</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1998</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Viroptic</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1998</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HSV</td></tr><tr><td align="left" rowspan="1" colspan="1">Palivizumab</td><td align="left" rowspan="1" colspan="1">Humanised mAb</td><td align="left" rowspan="1" colspan="1">1998</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">RSV</td></tr><tr><td align="left" rowspan="1" colspan="1">Amprenavir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1999</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Oseltamivir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1999</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">IAV, IBV</td></tr><tr><td align="left" rowspan="1" colspan="1">Zanamivir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">1999</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">IAV, IBV</td></tr><tr><td align="left" rowspan="1" colspan="1">Lopinavir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2000</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Docosanol</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2000</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HSV</td></tr><tr><td align="left" rowspan="1" colspan="1">Valganciclovir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2001</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">CMV</td></tr><tr><td align="left" rowspan="1" colspan="1">Tenofovir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2001</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV, HBV</td></tr><tr><td align="left" rowspan="1" colspan="1">Adefovir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2002</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HBV</td></tr><tr><td align="left" rowspan="1" colspan="1">Atazanavir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2003</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Emtricitabine</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2003</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Fosamprenavir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2003</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Entecavir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2005</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HBV</td></tr><tr><td align="left" rowspan="1" colspan="1">Tipranavir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2005</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Telbivudine</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2006</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HBV</td></tr><tr><td align="left" rowspan="1" colspan="1">Darunavir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2006</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Raltegravir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2007</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Etravirine</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2008</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Boceprevir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2011</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HCV</td></tr><tr><td align="left" rowspan="1" colspan="1">Telaprevir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2011</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HCV</td></tr><tr><td align="left" rowspan="1" colspan="1">Rilpivirine</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2011</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Simeprevir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2013</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HCV</td></tr><tr><td align="left" rowspan="1" colspan="1">Sofosbuvir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2013</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HCV</td></tr><tr><td align="left" rowspan="1" colspan="1">Dolutegravir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2013</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Peramivir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2014</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">IAV</td></tr><tr><td align="left" rowspan="1" colspan="1">Daclatasvir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2015</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HCV</td></tr><tr><td align="left" rowspan="1" colspan="1">Letermovir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2017</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">CMV</td></tr><tr><td align="left" rowspan="1" colspan="1">Doravirine</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2018</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Ibalizumab</td><td align="left" rowspan="1" colspan="1">Humanised mAb</td><td align="left" rowspan="1" colspan="1">2018</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">HIV</td></tr><tr><td align="left" rowspan="1" colspan="1">Baloxavir</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2018</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">IAV, IBV</td></tr><tr><td align="left" rowspan="1" colspan="1">Tecovirimat</td><td align="left" rowspan="1" colspan="1">Small molecule</td><td align="left" rowspan="1" colspan="1">2018</td><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">Smallpox</td></tr></tbody></table><table-wrap-foot id="cti21067-ntgp-0001"><fn id="cti21067-note-0001"><p>Approved combination therapies excluded.</p></fn><fn id="cti21067-note-0002"><p>CMV, cytomegalovirus; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; IAV, influenza A virus; IBV, influenza B virus; mAb, monoclonal antibody; RSV, respiratory syncytial virus; VZV, varicella‐zoster virus.</p></fn></table-wrap-foot><permissions><copyright-holder>John Wiley & Sons, Ltd</copyright-holder><license><license-p>This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.</license-p></license></permissions></table-wrap><p>While virus‐oriented approaches are efficacious, the genetic diversity of viruses often restricts such treatments to particular species or serotypes (Table <xref rid="cti21067-tbl-0001" ref-type="table">1</xref>). Furthermore, these antivirals are often costly and are ultimately susceptible to escape mutant selection. Simple point substitutions are often responsible for treatment failure,<xref rid="cti21067-bib-0004" ref-type="ref">4</xref>, <xref rid="cti21067-bib-0005" ref-type="ref">5</xref> while fitness costs associated with harbouring these substitutions may be trivially absorbed by the escaped strain upon accumulating compensatory adaptations.<xref rid="cti21067-bib-0006" ref-type="ref">6</xref> Tenofovir is an example of a highly effective single‐regimen treatment for chronic hepatitis B infection, a retro‐transcribing virus characterised by considerable genetic heterogeneity, by simultaneously imposing potent viral suppression, a high barrier for escape and reduced replicative fitness of escape strains. Despite these synergising effects, complex escape mutants harbouring multiple point substitutions in the viral reverse transcriptase have recently emerged.<xref rid="cti21067-bib-0007" ref-type="ref">7</xref> One way of enhancing treatment efficacy while minimising viral escape is to deploy existing antivirals as combination therapies, a strategy used extensively in current HIV (e.g. tenofovir/emtricitabine) and hepatitis C virus (HCV) treatment regimens.<xref rid="cti21067-bib-0004" ref-type="ref">4</xref>, <xref rid="cti21067-bib-0005" ref-type="ref">5</xref> While increasing the number of combinations increases the height of the escape barrier, proportional increases in treatment costs, adverse effects and counterindications make this strategy one of ever compounding challenges that ultimately remains exposed to the core problem of viral resistance. Treatment failure and the continuous need for the development of additional therapies are the realised costs of playing into such ‘strengths’ of virus evolution.</p><p>As obligate intracellular parasites, all viruses must subvert key resources of permissive hosts in order to replicate.<xref rid="cti21067-bib-0008" ref-type="ref">8</xref> Subverting multifunctional host proteins can confer significant fitness advantages by enabling RNA viruses to efficiently execute multiple steps in their replication strategy. Over time, these features are likely to be conserved within lineages and serve as foci of evolutionary convergence for viruses with a similar host range, while purifying selection eliminates steps rendered less efficient. Nevertheless, ideal targets of pathogenic viruses include those that are also vital to the host, thereby limiting its options for antiviral adaptation and driving more costly evolutionary innovation on its part. Similarly, the potential for adverse effects limits options for targeting such host proteins therapeutically.</p><p>Therapeutic drug availability, together with recent advances in areas including immunotherapy and precision medicine, is beginning to alleviate such constraints on host‐oriented approaches. Significantly, many of these technologies arose through examining evolutionarily diverse host–virus and immune interactions, which are being increasingly uncovered with the advent of mass next‐generation genome sequencing and machine learning‐assisted metagenomic analysis technologies. Furthermore, such interactions are increasingly found to perform crucial roles throughout our biosphere.<xref rid="cti21067-bib-0009" ref-type="ref">9</xref>, <xref rid="cti21067-bib-0010" ref-type="ref">10</xref>, <xref rid="cti21067-bib-0011" ref-type="ref">11</xref> As was once the case for the CRISPR/Cas bacterial immune system proteins now used in genome editing,<xref rid="cti21067-bib-0012" ref-type="ref">12</xref> these host–virus interactions often employ unique proteins of unknown function.<xref rid="cti21067-bib-0010" ref-type="ref">10</xref>, <xref rid="cti21067-bib-0013" ref-type="ref">13</xref>, <xref rid="cti21067-bib-0014" ref-type="ref">14</xref> This review examines how host–virus evolution may be leveraged towards solving disease and sustainability issues of our time. Multitasking or multifunctional host proteins as antiviral therapeutic targets, methods for targeting such proteins, vaccine design and neo‐virology as an emerging source of biotechnological innovation, will be discussed.</p></sec><sec id="cti21067-sec-0002"><title>Exploiting the information economy paradox in RNA virus evolution</title><p>RNA and retro‐transcribing virus genomes are highly versatile, with errors occurring 2–4 orders of magnitude more frequently than in high‐order eukaryotes.<xref rid="cti21067-bib-0015" ref-type="ref">15</xref> This, combined with their rapid replication cycle, imbues such viruses with two key strengths: enormous genetic diversity and rapid escape mutant selection. Nevertheless, this same process that enables remarkable genome plasticity also appears to limit the incorporation of new information with which to achieve more favorable host manipulation. There exists an inverse relationship between viral genome size and mutation rate, with large coronaviruses the only known RNA virus family to possess 3′‐exonuclease proofreading activity.<xref rid="cti21067-bib-0016" ref-type="ref">16</xref> Thus, the probability of acquiring a lethal mutation increases as a function of both polymerase infidelity and genome size. This suggests lengthening the genome to accommodate a larger repertoire of gene products with which to better manipulate the host comes with considerable fitness trade‐offs for RNA viruses. Indeed, excepting extremely small circular ssDNA viruses, RNA virus genomes are typically far shorter than DNA virus genomes in both average size (10.3 vs. 77.8 kb, respectively) and maximal size (51.3 vs. 2474 kb) and encode fewer proteins (1–28 vs. 1–1839; Figure <xref rid="cti21067-fig-0001" ref-type="fig">1</xref>). As a result, while various RNA viruses tolerate certain gene substitutions (e.g. recombinant reporter strains and segmented genome viruses),<xref rid="cti21067-bib-0017" ref-type="ref">17</xref> most are poorly tolerant of additions of new genetic information. Correspondingly, mutagenic nucleoside analogues exhibit broad‐spectrum antiviral activity by increasing the error rate in genome synthesis for nascent viral particles.<xref rid="cti21067-bib-0018" ref-type="ref">18</xref> This effectively reduces the optimal genome length of the virus for productive infection to below the threshold of viability, thereby driving the population to extinction. Therefore, while the core ‘strengths’ in RNA virus evolution arise because of the nature of their genetic material and its error‐prone mode of replication, these appear intractably coupled to limits on the size of information available to subvert their more complex hosts.</p><fig fig-type="Figure" xml:lang="en" id="cti21067-fig-0001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Genome and proteome size distribution of RNA versus DNA viruses. Data compiled using the NCBI Viral Genomes Resource,<xref rid="cti21067-bib-0116" ref-type="ref">116</xref> taxonomic ID 10239, accessed March 2019. Incomplete, unclassified and sub‐viral genomes excluded. <bold>(a)</bold> Histogram of virus genome sizes. Orange = RNA viruses; blue = DNA viruses; dashed line = single‐stranded genomes; solid line = double‐stranded genomes. <bold>(b)</bold> Range and average genome and proteome sizes of viruses plotted in <bold>a</bold>.</p></caption><graphic id="nlm-graphic-3" xlink:href="CTI2-8-e1067-g001"></graphic></fig><p>RNA virus evolution attempts to resolve this information economy paradox by extensively employing functional genomic secondary structures and noncoding regions, genome segmentation, compression (e.g. RNA editing, overprinting and frameshift reading) and gene product pleiotropy or multifunctionality (e.g. intrinsically disordered proteins).<xref rid="cti21067-bib-0017" ref-type="ref">17</xref>, <xref rid="cti21067-bib-0019" ref-type="ref">19</xref>, <xref rid="cti21067-bib-0020" ref-type="ref">20</xref>, <xref rid="cti21067-bib-0021" ref-type="ref">21</xref> Yet another way is to manipulate host cell factors that are themselves multi‐interacting or multifunctional ‘hubs’ of cellular activity,<xref rid="cti21067-bib-0022" ref-type="ref">22</xref> whereby a single viral gene product subverts a single host factor to achieve net favorable control over numerous cellular processes. This can enable the virus to extract maximum utility from its informationally limited genome at minimal informational cost. Multiplying this effect across several viral and/or host gene products may enable the virus to extract a substantial ‘return on investment’ in terms of replicative fitness.</p><p>Despite facilitating viral infectivity, these solutions to the information economy paradox cut both ways. Imbricated dependency on multifunctional host proteins for various key replication steps creates vulnerabilities that may be exploited for highly efficacious antiviral therapies. For example, denying such host proteins to the virus may disrupt multiple key elements in its replication strategy. Where these proteins represent foci of evolutionary convergence, such therapies may yield robust, broad‐spectrum antiviral activity. The degree of innovation required to circumvent such a therapy and, especially in the case of RNA viruses, the informational barrier to realising this innovation may be high. Escape mutants that emerge may be forced to overcome multiple deficiencies simultaneously and suffer compounding fitness penalties in the process. Furthermore, host‐oriented approaches present a much larger list of potential therapeutic targets than the dozen or so gene products produced by most human‐infective RNA viruses, many of which are challenging targets in the first instance because of genetic diversity and intrinsic protein disorder.<xref rid="cti21067-bib-0019" ref-type="ref">19</xref> Given the higher fidelity of DNA versus RNA replication, host therapeutic targets may prove resilient to certain mechanisms of viral resistance. Altogether, these advantages may reduce antiviral development costs over the long term, allowing for greater treatment accessibility and faster development of future therapies. But which host proteins are sufficiently multifunctional? And how might these present viable therapeutic substrates?</p></sec><sec id="cti21067-sec-0003"><title>Multifunctional host proteins as potential antiviral targets</title><p>To canvass potential therapeutic targets, the 282 most multifunctional human proteins identified to date were used to interrogate available protein interaction data (Figure <xref rid="cti21067-fig-0002" ref-type="fig">2</xref>). Strikingly, 77% (216/282) of these have been experimentally determined to interact with at least one viral protein (Supplementary table <xref rid="cti21067-tbl-0001" ref-type="table">1</xref>). Of these, 74% interact with at least one ssRNA viral protein, highlighting how multifunctional host proteins represent key ssRNA viral manipulation targets. The three highly multifunctional host proteins targeted by the greatest diversity of ssRNA virus families are as follows: heat‐shock protein 90a (HSP90a), HSP7C and polyadenylate‐binding protein 1 (PABP1; Figure <xref rid="cti21067-fig-0002" ref-type="fig">2</xref>). These proteins appear to serve as key drivers of convergence between diverse human‐infective viruses, suggesting these are potential targets of broad‐spectrum antivirals. Additional targets of significant interest include alpha‐enolase, heat‐shock protein beta‐1 (HSPB1, also termed HSP27), heterogeneous nuclear ribonucleoprotein K (hnRNPK), histone acetyltransferase (HAT) p300, vimentin, vitamin K epoxide reductase complex subunit 1 (VKORC1) and tumor antigen p53 (Figure <xref rid="cti21067-fig-0002" ref-type="fig">2</xref> and Table <xref rid="cti21067-tbl-0002" ref-type="table">2</xref>). Diverse RNA viruses targeting these proteins, as well as possible therapeutic avenues, are discussed below.</p><fig fig-type="Figure" xml:lang="en" id="cti21067-fig-0002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Interaction map of the 10 most multifunctional human proteins targeted most frequently by viruses. The 282 most multifunctional human proteins<xref rid="cti21067-bib-0117" ref-type="ref">117</xref> were used to interrogate available protein interaction data with the VirHostNet tool.<xref rid="cti21067-bib-0118" ref-type="ref">118</xref> Top 10 virus‐interacting multifunctional host proteins represented in black filled circles and labelled in bold type. Black lines depict host–host protein interactions, and red lines depict host–virus protein interactions. ssRNA viral protein interacting partners represented as coloured filled circles (clockwise from the top: yellow = Flaviviridae, purple = Orthomyxoviridae; light blue = Coronaviridae; dark blue = Togaviridae; grey = Retroviridae; dark green = Filoviridae; red = Pneumoviridae; light green = Arenaviridae; teal = Peribunyaviridae; orange = Phenuiviridae; white = Paramyxoviridae). The complete data set is shown in Supplementary table <xref rid="cti21067-sup-0001" ref-type="supplementary-material">1</xref>.</p></caption><graphic id="nlm-graphic-5" xlink:href="CTI2-8-e1067-g002"></graphic></fig><table-wrap id="cti21067-tbl-0002" xml:lang="en" orientation="portrait" position="float"><label>Table 2</label><caption><p>Approved, investigational or experimental bioactive compounds for the 25 most multifunctional host proteins targeted most frequently by viruses</p></caption><table frame="hsides" rules="groups"><col style="border-right:solid 1px #000000" span="1"></col><col style="border-right:solid 1px #000000" span="1"></col><col style="border-right:solid 1px #000000" span="1"></col><col style="border-right:solid 1px #000000" span="1"></col><col style="border-right:solid 1px #000000" span="1"></col><thead valign="top"><tr style="border-bottom:solid 1px #000000"><th align="left" valign="top" rowspan="1" colspan="1">Rank</th><th align="center" valign="top" rowspan="1" colspan="1">UniProt</th><th align="center" valign="top" rowspan="1" colspan="1">Multitasking host proteins</th><th align="center" valign="top" rowspan="1" colspan="1">Approved, investigational or experimental host protein‐targeting drugs</th><th align="center" valign="top" rowspan="1" colspan="1">Host protein‐targeting RNA viruses</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">P06733</td><td align="left" rowspan="1" colspan="1">Alpha‐enolase</td><td align="left" rowspan="1" colspan="1">Artenimol, AP‐III‐a4/ENOblock</td><td align="left" rowspan="1" colspan="1">AlkV, DenV, HCV, IAV, KunV, SARS‐CoV, TBEV</td></tr><tr><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">P04637</td><td align="left" rowspan="1" colspan="1">Tumor antigen p53</td><td align="left" rowspan="1" colspan="1">Acetylsalicylic Acid, AZD 3355, 1‐(9‐ethyl‐9H‐carbazol‐3‐yl)‐<italic>N</italic>‐methylmethanamine</td><td align="left" rowspan="1" colspan="1">HCV, HIV‐1, MV, RV, ZEboV</td></tr><tr><td align="left" rowspan="1" colspan="1">3</td><td align="left" rowspan="1" colspan="1">P61978</td><td align="left" rowspan="1" colspan="1">Heterogeneous nuclear ribonucleoprotein K</td><td align="left" rowspan="1" colspan="1">Artenimol, Bortezomib, Phenethyl Isothiocyanate</td><td align="left" rowspan="1" colspan="1">ChikV, HCV, HIV‐1, IAV, MV, SFV, SinV, ZEboV</td></tr><tr><td align="left" rowspan="1" colspan="1">4</td><td align="left" rowspan="1" colspan="1">Q9BQB6</td><td align="left" rowspan="1" colspan="1">Vitamin K epoxide reductase complex subunit 1</td><td align="left" rowspan="1" colspan="1">Menadione, Warfarin</td><td align="left" rowspan="1" colspan="1">IAV, SARS‐CoV</td></tr><tr><td align="left" rowspan="1" colspan="1">5</td><td align="left" rowspan="1" colspan="1">Q09472</td><td align="left" rowspan="1" colspan="1">Histone acetyltransferase p300</td><td align="left" rowspan="1" colspan="1">Anacardic Acid, Curcumin, Demethoxycurcumin, Garcinol, Histone Acetyltransferase Inhibitor II, A‐485, C646, L002, Lys‐CoA</td><td align="left" rowspan="1" colspan="1">HCV, HIV‐1, HTLV</td></tr><tr><td align="left" rowspan="1" colspan="1">6</td><td align="left" rowspan="1" colspan="1">P04792</td><td align="left" rowspan="1" colspan="1">Heat‐shock protein beta‐1</td><td align="left" rowspan="1" colspan="1">Apatorsen, Artenimol, J2, Phenethyl Isothiocyanate</td><td align="left" rowspan="1" colspan="1">HIV‐1, IAV, LCMV</td></tr><tr><td align="left" rowspan="1" colspan="1">7</td><td align="left" rowspan="1" colspan="1">P07900</td><td align="left" rowspan="1" colspan="1">Heat‐shock protein 90‐alpha</td><td align="left" rowspan="1" colspan="1">Aminoxyrone, Ganetespib, Geldanamycin, Luminespib, Onalespib, Retaspimycin, Tanespimycin/17‐AAG, AUY922, BIIB021, IPI‐493, SNX‐5422, STA‐9090, XL888</td><td align="left" rowspan="1" colspan="1">BunV, HCV, HIV‐1, IAV, LCMV, MV, RVFV</td></tr><tr><td align="left" rowspan="1" colspan="1">8</td><td align="left" rowspan="1" colspan="1">P08670</td><td align="left" rowspan="1" colspan="1">Vimentin</td><td align="left" rowspan="1" colspan="1">Artenimol, Calyculin A, Epigallocatechin Gallate, Okadaic Acid, Phenethyl Isothiocyanate, Salinomycin, SB431542, Withaferin A</td><td align="left" rowspan="1" colspan="1">AlkV, ChikV, DenV, HCV, HIV‐1, MV, SFV, SinV, TBEV</td></tr><tr><td align="left" rowspan="1" colspan="1">9</td><td align="left" rowspan="1" colspan="1">P11940</td><td align="left" rowspan="1" colspan="1">Polyadenylate‐binding protein 1</td><td align="left" rowspan="1" colspan="1">Artenimol</td><td align="left" rowspan="1" colspan="1">HIV‐1, IAV, KunV, LCMV, MV, ReoV, SinV, ZEboV</td></tr><tr><td align="left" rowspan="1" colspan="1">10</td><td align="left" rowspan="1" colspan="1">P11142</td><td align="left" rowspan="1" colspan="1">Heat‐shock cognate 71 kDa protein</td><td align="left" rowspan="1" colspan="1">Artenimol, Dasatinib</td><td align="left" rowspan="1" colspan="1">HCV, HIV‐1, IAV, LCMV, RSV, SinV, ZEboV</td></tr><tr><td align="left" rowspan="1" colspan="1">11</td><td align="left" rowspan="1" colspan="1">Q93062</td><td align="left" rowspan="1" colspan="1">RNA‐binding protein with multiple splicing</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">HTLV, IAV</td></tr><tr><td align="left" rowspan="1" colspan="1">12</td><td align="left" rowspan="1" colspan="1">P12004</td><td align="left" rowspan="1" colspan="1">Proliferating cell nuclear antigen</td><td align="left" rowspan="1" colspan="1">Acetylsalicyclic Acid, Liothyronine</td><td align="left" rowspan="1" colspan="1">HIV‐1, IAV, ZEboV</td></tr><tr><td align="left" rowspan="1" colspan="1">13</td><td align="left" rowspan="1" colspan="1">P08238</td><td align="left" rowspan="1" colspan="1">Heat‐shock protein 90‐beta</td><td align="left" rowspan="1" colspan="1">Geldanamycin, Tanespimycin/17‐AAG, CNF1010, SNX‐5422</td><td align="left" rowspan="1" colspan="1">DenV, HCV, KunV, RVFV</td></tr><tr><td align="left" rowspan="1" colspan="1">14</td><td align="left" rowspan="1" colspan="1">Q14160</td><td align="left" rowspan="1" colspan="1">Protein scribble homolog</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">AlkV, HTLV, IAV, RabV, TBEV</td></tr><tr><td align="left" rowspan="1" colspan="1">15</td><td align="left" rowspan="1" colspan="1">P04406</td><td align="left" rowspan="1" colspan="1">Glyceraldehyde‐3‐phosphate dehydrogenase</td><td align="left" rowspan="1" colspan="1">Adenosine‐5‐Diphosphoribose, Artenimol, Thionicotinamide‐Adenine‐Dinucleotide, Xanthinol, 4‐(2‐Aminoethyl)Benzenesulfonyl Fluoride</td><td align="left" rowspan="1" colspan="1">HeV, HIV, LCMV</td></tr><tr><td align="left" rowspan="1" colspan="1">16</td><td align="left" rowspan="1" colspan="1">Q8N448</td><td align="left" rowspan="1" colspan="1">Ligand of numb protein X2</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">HTLV, IAV</td></tr><tr><td align="left" rowspan="1" colspan="1">17</td><td align="left" rowspan="1" colspan="1">Q08379</td><td align="left" rowspan="1" colspan="1">Golgin subfamily A member 2</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">HCV, RSV</td></tr><tr><td align="left" rowspan="1" colspan="1">18</td><td align="left" rowspan="1" colspan="1">P62258</td><td align="left" rowspan="1" colspan="1">14‐3‐3 protein epsilon</td><td align="left" rowspan="1" colspan="1">Fusicoccin, Phenethyl Isothiocyanate</td><td align="left" rowspan="1" colspan="1">HCV, HIV‐1, IAV, NiV, SinV</td></tr><tr><td align="left" rowspan="1" colspan="1">19</td><td align="left" rowspan="1" colspan="1">P22736</td><td align="left" rowspan="1" colspan="1">Nuclear receptor subfamily 4 group A member 1</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">HCV</td></tr><tr><td align="left" rowspan="1" colspan="1">20</td><td align="left" rowspan="1" colspan="1">P27986</td><td align="left" rowspan="1" colspan="1">PI3K regulatory subunit alpha</td><td align="left" rowspan="1" colspan="1">Enzastaurin, Isoprenaline, Wortmannin, SF1126</td><td align="left" rowspan="1" colspan="1">HEV, HIV, IAV</td></tr><tr><td align="left" rowspan="1" colspan="1">21</td><td align="left" rowspan="1" colspan="1">P63279</td><td align="left" rowspan="1" colspan="1">Small ubiquitin‐like modifier‐conjugating enzyme Ubc9</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">DenV, HIV‐1</td></tr><tr><td align="left" rowspan="1" colspan="1">22</td><td align="left" rowspan="1" colspan="1">Q99816</td><td align="left" rowspan="1" colspan="1">Tumor susceptibility gene 101 protein</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">HCV, HEV, HeV, HIV‐1, HIV‐2, HSRV, HTLV</td></tr><tr><td align="left" rowspan="1" colspan="1">23</td><td align="left" rowspan="1" colspan="1">Q13200</td><td align="left" rowspan="1" colspan="1">26S proteasome non‐ATPase regulatory subunit 2</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">DenV, HCV, HIV‐1, IAV, MV</td></tr><tr><td align="left" rowspan="1" colspan="1">24</td><td align="left" rowspan="1" colspan="1">P14618</td><td align="left" rowspan="1" colspan="1">Pyruvate kinase PKM</td><td align="left" rowspan="1" colspan="1">Artenimol</td><td align="left" rowspan="1" colspan="1">DenV, HCV, IAV, LCMV</td></tr><tr><td align="left" rowspan="1" colspan="1">25</td><td align="left" rowspan="1" colspan="1">Q9UNE7</td><td align="left" rowspan="1" colspan="1">E3 ubiquitin–protein ligase CHIP</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">DenV, HIV‐1, IAV</td></tr></tbody></table><table-wrap-foot id="cti21067-ntgp-0002"><fn id="cti21067-note-0003"><p>Proteins ranked according to total number of viral interacting partners.</p></fn><fn id="cti21067-note-0004"><p>RNA viruses shown: AlkV, Alkhumra haemorrhagic fever virus; BunV, Bunyamwera virus; ChikV, chikungunya virus; DenV, dengue virus; HCV, hepatitis C virus; HEV, hepatitis E virus; HeV, Hendra virus; HIV, human immunodeficiency virus; HSRV, human spumaretrovirus; HTLV, human T‐lymphotropic virus; IAV, influenza A virus; KunV, Kunjin virus; LCMV, lymphocytic choriomeningitis virus; MV, measles virus; NiV; Nipah virus; RabV, rabies virus; ReoV, reovirus; RSV, respiratory syncytial virus; RVFV, Rift Valley fever virus; SARS‐CoV, severe acute respiratory syndrome‐coronavirus; SFV, Semliki Forest virus; SinV, Sindbis virus; TBEV, tick‐borne encephalitis virus; ZEboV, Zaire Ebola virus.</p></fn></table-wrap-foot><permissions><copyright-holder>John Wiley & Sons, Ltd</copyright-holder><license><license-p>This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.</license-p></license></permissions></table-wrap><sec id="cti21067-sec-0004"><title>Measles virus (MV)</title><p>Measles virus is an extremely contagious and virulent pathogen undergoing a recent global resurgence. The non‐structural V protein targets the single largest number of highly multitasking human proteins: HSP90a, PABP1, vimentin, hnRNPK and p53 (Figure <xref rid="cti21067-fig-0002" ref-type="fig">2</xref>). In addition to V's established roles in suppressing multiple components of host interferon (IFN) signalling,<xref rid="cti21067-bib-0023" ref-type="ref">23</xref> these interactions may allow MV to interface with the cytoskeleton (vimentin) and subvert numerous host cell processes including cell cycle (p53, hnRNPK), protein translation (PABP1), RNA metabolism (PABP1, hnRNPK), and transcription and protein expression (HSP90a). V is produced by editing of the <italic>P</italic> gene transcript, which also overlaps with the <italic>C</italic> gene. The largest number of amino acid substitutions between wild‐type MV and attenuated vaccine strains occurs within the <italic>P</italic>/<italic>V</italic>/<italic>C</italic> gene region,<xref rid="cti21067-bib-0024" ref-type="ref">24</xref> suggesting changes in this region serve an important basis for natural attenuation. Since attenuated MV strains possess very limited capacity for reversion,<xref rid="cti21067-bib-0024" ref-type="ref">24</xref> MV strains engineered to harbour defects in V binding to these host proteins may be suitable designer vaccine candidates. As discussed in the following sections, re‐purposing existing host‐targeting bioactive compounds as antivirals may also yield therapeutic results.</p></sec><sec id="cti21067-sec-0005"><title>Human immunodeficiency virus (HIV)</title><p>The HIV‐1 accessory protein viral infectivity factor (Vif), also crucial in suppressing host immunity,<xref rid="cti21067-bib-0025" ref-type="ref">25</xref> targets all three highly multitasking heat‐shock proteins HSP90a, HSPB1/HSP27 and HSP7C (Figure <xref rid="cti21067-fig-0002" ref-type="fig">2</xref>). This suggests subversion of the cellular protein quality control pathways or HSP‐mediated gene expression is vital in the HIV‐1 replication cycle. Accordingly, HSP90 inhibitors 17‐AAG/tanespimycin and AUY922 (Table <xref rid="cti21067-tbl-0002" ref-type="table">2</xref>) were recently shown to inhibit HIV‐1 transcription and suppress viral rebound in a humanised mouse model.<xref rid="cti21067-bib-0026" ref-type="ref">26</xref> Although these and other HSP90 inhibitors have encountered efficacy and toxicity issues during clinical trials as anticancer therapies, aminoxyrone is novel, first‐in‐class HSP90 inhibitor that appears to alleviate both issues.<xref rid="cti21067-bib-0027" ref-type="ref">27</xref> Its efficacy as an antiviral or antiretroviral therapeutic has yet to be studied. Inhibitors of HSPB1 and HSP7C (Table <xref rid="cti21067-tbl-0002" ref-type="table">2</xref>) represent additional avenues for effective host‐oriented antiretroviral therapies that have also yet to be explored.</p><p>HIV‐1 tat (transactivating regulatory protein), which is required for efficient viral gene transcription,<xref rid="cti21067-bib-0028" ref-type="ref">28</xref> targets PABP1, p53 and HAT p300 (Figure <xref rid="cti21067-fig-0002" ref-type="fig">2</xref>). The latter protein is further manipulated by two additional HIV‐1 proteins, viral protein R (Vpr) and Pol (DNA polymerase), as well as the transactivating regulatory protein (Tax) of human T‐lymphotropic virus (HTLV; Figure <xref rid="cti21067-fig-0002" ref-type="fig">2</xref>), plausibly representing a conserved mechanism of host subversion. HATs and histone deacetylases (HDACs) are crucial effectors in epigenetic modulation of gene expression, connecting a large number of cell signalling inputs with transcriptional outputs through histone post‐translational modifications.<xref rid="cti21067-bib-0029" ref-type="ref">29</xref> HAT and HDAC inhibitors have been shown to suppress viral transcription (‘kill’) and re‐activate latent virus (‘shock‐and‐kill’), respectively,<xref rid="cti21067-bib-0030" ref-type="ref">30</xref>, <xref rid="cti21067-bib-0031" ref-type="ref">31</xref> suggesting epigenetic remodulation of host gene activity is exceptionally important in the replication strategy of HIV‐1 and other retroviruses. Alternatively, retroviral proteins may block or usurp the enzymatic activity of HAT p300 to direct acetylation of viral or other host proteins, which has been suggested for Tat.<xref rid="cti21067-bib-0032" ref-type="ref">32</xref> The interactions between HAT p300 and HIV‐1 proteins Tat, Vpr and Pol (Figure <xref rid="cti21067-fig-0002" ref-type="fig">2</xref>), together with the large number of HAT p300 inhibitors currently available (Table <xref rid="cti21067-tbl-0002" ref-type="table">2</xref>), expand the possibilities for targeting HAT p300 in host‐oriented antiretroviral therapies.</p></sec><sec id="cti21067-sec-0006"><title>Influenza A virus (IAV)</title><p>Influenza A virus (IAV) engages four gene products to manipulate two highly multifunctional host proteins. HSP90a is targeted by NS1 (virulence factor), PB2 (transcription and capping) and RNA‐dependent RNA polymerase (RdRP), while alpha‐enolase is targeted by NS1 as well as NS2/NEP (vRNP nuclear export; Figure <xref rid="cti21067-fig-0002" ref-type="fig">2</xref>). The NS1 proteins of avian influenza strain H5N1 as well as H3N2 reportedly bind HSP90 to modulate caspase‐mediated apoptosis.<xref rid="cti21067-bib-0033" ref-type="ref">33</xref> In addition to impairing HIV‐1 replication,<xref rid="cti21067-bib-0030" ref-type="ref">30</xref>, <xref rid="cti21067-bib-0031" ref-type="ref">31</xref> HSP90 inhibitors reportedly inhibit IAV replication without apparent cytotoxicity <italic>in vitro</italic>.<xref rid="cti21067-bib-0034" ref-type="ref">34</xref> It will be of interest to examine whether these effects translate <italic>in vivo</italic> using next‐generation HSP90 inhibitors<xref rid="cti21067-bib-0027" ref-type="ref">27</xref> (Table <xref rid="cti21067-tbl-0002" ref-type="table">2</xref>).</p><p>Influenza A virus, together with SARS‐CoV and multiple flaviviruses, also targets alpha‐enolase, an enzyme with roles in glycolysis, cell growth and immunity (Figure <xref rid="cti21067-fig-0002" ref-type="fig">2</xref>). A novel inhibitor, AP‐III‐a4 (ENOblock), was recently developed with the interesting property of blocking the non‐glycolytic functions of alpha‐enolase (Table <xref rid="cti21067-tbl-0002" ref-type="table">2</xref>). While this drug shows promise in treating obesity in animal models,<xref rid="cti21067-bib-0035" ref-type="ref">35</xref> its antiviral effects remain unexplored. This warrants further study as a potential host‐oriented antiviral approach to IAV and other viral infections.</p></sec><sec id="cti21067-sec-0007"><title>Togaviruses</title><p>Similarly, by committing four of its proteins to manipulating hnRNPK (Figure <xref rid="cti21067-fig-0002" ref-type="fig">2</xref>), Sindbis virus (SinV) reveals this multifunctional host protein to be crucial in its replication strategy. Co‐immunoprecipitation experiments suggest hnRNPK associates with the SinV polyprotein processing products nsp1 (methyl/guanylyltransferase), nsp2 (helicase/protease) and nsp3 (regulatory component) and may be required for viral transcription.<xref rid="cti21067-bib-0036" ref-type="ref">36</xref> Other <italic>Togaviridae</italic> members including Semliki Forest virus (SFV) and chikungunya virus (ChikV) also manipulate hnRNPK (Figure <xref rid="cti21067-fig-0002" ref-type="fig">2</xref>), suggesting this host protein serves multiple, evolutionarily conserved roles in togavirus replication. While this hints at a potential therapeutic route against togaviruses, there are currently no selective hnRNPK‐targeting drugs available (Table <xref rid="cti21067-tbl-0002" ref-type="table">2</xref>). hnRNPK is also tumor suppressor, with mutated or constitutively downregulated hnRNPK being associated with tumorigenesis.<xref rid="cti21067-bib-0037" ref-type="ref">37</xref> Nevertheless, short‐term therapeutic targeting of hnRNPK as an antiviral strategy has yet to be explored.</p><p>Viral infection often induces cytoskeletal remodelling, resulting in cytopathic morphologies including syncytia and tumor‐like aggregates. Cells treated with actin depolymerising agents such as cytochalasin D show drastic reductions in production of numerous viruses,<xref rid="cti21067-bib-0038" ref-type="ref">38</xref> although such agents, by their nature, have limited therapeutic applicability. Vimentin, a component of intermediate filaments, is manipulated by SinV, SFV and ChikV, together with MV as previously mentioned, and the flaviviruses DenV, HCV, tick‐borne encephalitis virus (TBEV), Alkhumra haemorrhagic fever virus (AlkV) and Kunjin virus (KunV)/West Nile virus (WNV; Figure <xref rid="cti21067-fig-0002" ref-type="fig">2</xref>). Vimentin is reported to play a key role in replication complex assembly and modulating viral protein expression levels in DenV and HCV infection, respectively.<xref rid="cti21067-bib-0039" ref-type="ref">39</xref>, <xref rid="cti21067-bib-0040" ref-type="ref">40</xref> Withaferin D targets the soluble form of vimentin<xref rid="cti21067-bib-0041" ref-type="ref">41</xref> (Table <xref rid="cti21067-tbl-0002" ref-type="table">2</xref>) and has anticancer properties, although the effects of vimentin‐targeting drugs in the context of infection have yet to be extensively studied.</p></sec><sec id="cti21067-sec-0008"><title>Flaviviruses</title><p>Numerous flaviviruses including DenV, HCV, TBEV, AlkV and KunV/WNV manipulate alpha‐enolase (Figure <xref rid="cti21067-fig-0002" ref-type="fig">2</xref>), an enzyme with many functions including catalysing the penultimate step in ATP synthesis via glycolysis. While viruses often re‐program cellular metabolic pathways, DenV drastically increases the rate of glycolysis to support its own replication. Metabolic acidosis is often associated with severe disease and may correlate with the subcellular redistribution of viral proteins to further compromise host stress responses.<xref rid="cti21067-bib-0042" ref-type="ref">42</xref> Thus, DenV‐infected patients who are simultaneously hyperglycaemic (e.g. diabetics) are at greater risk of severe disease.<xref rid="cti21067-bib-0043" ref-type="ref">43</xref> Accordingly, inhibiting glycolysis impairs replication of DenV and other flaviviruses <italic>in vitro</italic>.<xref rid="cti21067-bib-0044" ref-type="ref">44</xref>, <xref rid="cti21067-bib-0045" ref-type="ref">45</xref> In this context, it would be of interest to examine whether alpha‐enolase inhibitors such as AP‐III‐a4/ENOblock (Table <xref rid="cti21067-tbl-0002" ref-type="table">2</xref>), which blocks the non‐glycolytic functions of alpha‐enolase as mentioned previously, may block subversion of this key enzyme by flaviviruses <italic>in vivo</italic>.</p></sec><sec id="cti21067-sec-0009"><title>Other targets</title><p>One unexpected multiple viral target is VKORC1, an enzyme highly expressed in liver and crucial in activating blood clotting factors.<xref rid="cti21067-bib-0046" ref-type="ref">46</xref> While relatively fewer RNA viruses target VKORC1 (Figure <xref rid="cti21067-fig-0002" ref-type="fig">2</xref>), it is targeted by several DNA viruses including the hepatotropic Epstein–Barr virus. It would be of interest to examine what effects, if any, infection by such viruses have in the context of treatment with vitamin K or VKORC1‐targeting drugs such as warfarin (Table <xref rid="cti21067-tbl-0002" ref-type="table">2</xref>).</p><p>While not themselves multifunctional, ubiquitin and ubiquitin‐like modifiers undergo covalent and non‐covalent association with other proteins and exert plethoric effects on their function, abundance or subcellular distribution. Thus, manipulating the ubiquitin and ubiquitin‐like post‐translational modification machinery, or the proteasome itself, also enables viruses to subvert multiple cellular processes.<xref rid="cti21067-bib-0008" ref-type="ref">8</xref> Indeed, most multitasking host proteins examined here undergo extensive post‐translational modification.<xref rid="cti21067-bib-0047" ref-type="ref">47</xref> Numerous multitasking proteins of the ubiquitin–proteasome system, as well as ubiquitin and ubiquitin‐like modifiers, are key targets of multiple viruses. These targets include the proteasome regulatory subunit PSMD2; the E3 ubiquitin–protein ligase CHIP, which modulates the activity of numerous protein chaperones including HSP90<xref rid="cti21067-bib-0048" ref-type="ref">48</xref>; and the small ubiquitin‐like modifier‐conjugating enzyme Ubc9, which regulates numerous cellular functions including cell cycle by modifying p53<xref rid="cti21067-bib-0049" ref-type="ref">49</xref> (Table <xref rid="cti21067-tbl-0002" ref-type="table">2</xref> and Supplementary table <xref rid="cti21067-sup-0001" ref-type="supplementary-material">1</xref>). Numerous inhibitors of the proteasome, ubiquitin E1, E2 or E3 enzymes and deubiquitinating enzymes are currently in clinical trials or approved for use as anticancer agents.<xref rid="cti21067-bib-0050" ref-type="ref">50</xref> Therapeutically modulating the ubiquitin–proteasome system may present an indirect method of targeting multitasking proteins that are otherwise ‘undruggable’ at present (Table <xref rid="cti21067-tbl-0002" ref-type="table">2</xref>).</p></sec></sec><sec id="cti21067-sec-0010"><title>Challenges and strategies in targeting multifunctional host proteins</title><p>Therapeutically targeting host proteins that converge various cellular processes can elicit unwanted effects. This challenge is familiar to the very viruses that exploit such proteins in the first instance, yet their success also implies its soundness as an antiviral strategy. Illustrating that multifunctional host proteins can be ‘druggable’, 48% of the 694 human multitasking proteins annotated by Franco‐Serrano <italic>et al</italic>.<xref rid="cti21067-bib-0051" ref-type="ref">51</xref> are already targets of known compounds, compared with 9.8% of all 26 199 human proteins listed in UniProt. This also suggests potential for re‐purposing existing drugs for host‐oriented antiviral therapy (Table <xref rid="cti21067-tbl-0002" ref-type="table">2</xref>).</p><p>Since viruses typically infect and replicate best in only a limited set of host tissues, delivering therapies to specific tissues may mitigate adverse effects. Synthetic lipid nanoparticles (LNPs) protect and deliver small RNAs for RNAi‐based therapy as well as synthetic vaccines and bioactive compounds,<xref rid="cti21067-bib-0052" ref-type="ref">52</xref>, <xref rid="cti21067-bib-0053" ref-type="ref">53</xref>, <xref rid="cti21067-bib-0054" ref-type="ref">54</xref>, <xref rid="cti21067-bib-0055" ref-type="ref">55</xref>, <xref rid="cti21067-bib-0056" ref-type="ref">56</xref> while modified viruses or virus‐like particles deliver RNA interference (RNAi)‐based therapies as well as nucleases and DNA for gene therapy.<xref rid="cti21067-bib-0057" ref-type="ref">57</xref>, <xref rid="cti21067-bib-0058" ref-type="ref">58</xref> Despite additional challenges as outlined below, these technologies are currently applied to deliver specific treatments for viral infection, cardiovascular disease, inherited genetic disorders and cancer immunotherapy in animal models and humans.<xref rid="cti21067-bib-0052" ref-type="ref">52</xref>, <xref rid="cti21067-bib-0053" ref-type="ref">53</xref>, <xref rid="cti21067-bib-0054" ref-type="ref">54</xref>, <xref rid="cti21067-bib-0055" ref-type="ref">55</xref>, <xref rid="cti21067-bib-0056" ref-type="ref">56</xref>, <xref rid="cti21067-bib-0057" ref-type="ref">57</xref></p><sec id="cti21067-sec-0011"><title>RNA‐based therapies</title><sec id="cti21067-sec-0012"><title>miRNA and siRNA biogenesis</title><p>The last eukaryote common ancestor likely possessed an RNAi system utilising endogenous or exogenous noncoding RNAs (ncRNAs) and an RdRP.<xref rid="cti21067-bib-0059" ref-type="ref">59</xref> However, host–pathogen interactions have shaped RNAi utilisation throughout eukaryote diversification. Budding yeasts, including the prototypical <italic>Saccharomyces</italic> <italic>cerevisiae</italic>, harbouring endemic dsRNA viruses of the Totiviridae family lost RNAi while other yeasts lacking such viruses retained RNAi.<xref rid="cti21067-bib-0060" ref-type="ref">60</xref> With the rise of jawed vertebrates, RdRP was lost while IFN was gained, enabling large, complex life to coordinate multifurcated, system‐wide responses to infection and eventually supplanted RNAi as the primary antiviral defence mechanism in animals.<xref rid="cti21067-bib-0061" ref-type="ref">61</xref>, <xref rid="cti21067-bib-0062" ref-type="ref">62</xref> Nevertheless, ncRNAs continue to perform crucial roles in fundamental mammalian cellular processes including pre‐mRNA processing via spliceosomes (e.g. small nuclear RNA; snRNA). Small interfering RNA (siRNA) and microRNA (miRNA) are those most commonly applied in current RNAi biotechnology.</p><p>In addition to their sequence and tissue specificity, ncRNA function is determined by their expression level, post‐transcriptional processing and modification, protein interacting partners and subcellular compartmentalisation, as outlined below. miRNA is selectively expressed in all human tissues, with 1917 miRNAs currently annotated in the miRBase database predicted to control transcription of > 60% of human protein‐coding genes.<xref rid="cti21067-bib-0063" ref-type="ref">63</xref>, <xref rid="cti21067-bib-0064" ref-type="ref">64</xref> In the nucleus, primary miRNA transcripts are processed into 60–80 nt pre‐miRNA by the Microprocessor complex comprising the RNase‐III enzyme Drosha and DGCR8, the latter of which also associates with exosomes<xref rid="cti21067-bib-0065" ref-type="ref">65</xref> which play crucial roles in RNA processing and surveillance. Alternatively, mirtron miRNAs are spliced directly from introns by the spliceosome, independently of Drosha.<xref rid="cti21067-bib-0066" ref-type="ref">66</xref> Exportin‐5 transports pre‐miRNA into the cytosol, while a Drosha‐independent miRNA subset is reportedly transported in an exportin‐1‐/CRM1‐dependent manner.<xref rid="cti21067-bib-0067" ref-type="ref">67</xref></p><p>In the cytosol, the RNase‐III enzyme Dicer excises ~ 20–23 nt double‐stranded miRNA as well as endogenous and exogenous siRNA fragments.<xref rid="cti21067-bib-0068" ref-type="ref">68</xref> All RNase‐III cleavage products are characterised by a 2 nt 3′ overhang together with 5′‐monophosphorylated and 3′‐hydroxyated ends. The strand with the thermodynamically more stable 5′ end is usually degraded, while the remaining ssRNA guide strand is loaded onto Argonaute proteins. Together, these ribonucleoproteins form the RNA‐induced silencing complex (RISC).<xref rid="cti21067-bib-0069" ref-type="ref">69</xref> The endoribonuclease activity of Ago2 cleaves the target RNA to achieve post‐transcriptional repression,<xref rid="cti21067-bib-0070" ref-type="ref">70</xref> while other Argonaute proteins repress expression through non‐degradative mechanisms.</p><p>Exosomes and the exoribonuclease XRN1 are both required for full degradation of RISC cleavage products in <italic>Drosophila</italic>.<xref rid="cti21067-bib-0071" ref-type="ref">71</xref> Intriguingly, XRN1, which serves as a crucial viral restriction factor in totivirus‐harbouring (i.e. RNAi‐deficient) yeasts,<xref rid="cti21067-bib-0072" ref-type="ref">72</xref> and exosome core components RRP41, which associates with DGCR8,<xref rid="cti21067-bib-0065" ref-type="ref">65</xref> and RRP42 are identified here as among the most highly multitasking proteins most frequently manipulated by human‐infective viruses. Other such proteins include LSm3, a core component of U6 snRNA–protein complexes in spliceosomes,<xref rid="cti21067-bib-0073" ref-type="ref">73</xref>, <xref rid="cti21067-bib-0074" ref-type="ref">74</xref> and UPF2 (Supplementary table <xref rid="cti21067-sup-0001" ref-type="supplementary-material">1</xref>), a key mediator of the nonsense‐mediated mRNA quality control pathways that recruits endonucleases and other factors to regulate aberrant mRNA decay.<xref rid="cti21067-bib-0075" ref-type="ref">75</xref> Such interactions may enable evolutionarily diverse viruses to manipulate host/virus mRNA or ncRNA biogenesis and stability. The immune mechanisms and potential therapeutic applications of RNA post‐transcriptional control are discussed further by Yoshinaga and Takeuchi<xref rid="cti21067-bib-0119" ref-type="ref">119</xref> in another article in this Special Feature.</p></sec><sec id="cti21067-sec-0013"><title>Interactions with innate immunity</title><p>Toll‐like receptor 7 (TLR7) and TLR8 recognise extracellular ssRNA as short as 3 and 2 nt, respectively, and are activated to a greater extent in a sequence‐specific manner irrespective of end modifications.<xref rid="cti21067-bib-0076" ref-type="ref">76</xref>, <xref rid="cti21067-bib-0077" ref-type="ref">77</xref>, <xref rid="cti21067-bib-0078" ref-type="ref">78</xref> In a similar fashion, TLR3 recognises extracellular as well as endosomal dsRNA longer than 21 nt.<xref rid="cti21067-bib-0079" ref-type="ref">79</xref>, <xref rid="cti21067-bib-0080" ref-type="ref">80</xref> The retinoic acid‐inducible gene‐I (RIG‐I)‐like receptors sense intracellular RNA. These include the prototypical RIG‐I, which is activated by ssRNA as short as 10 nt harbouring a di‐ or tri‐phosphorylated 5′ end.<xref rid="cti21067-bib-0081" ref-type="ref">81</xref> MDA5 is activated by large RNA molecules, while LGP2 recognises RNA as short as 12 nt irrespective of phosphorylation or hydroxylation at the 5′ end. LGP2 activation supports MDA5‐dependent signalling while inhibiting both RIG‐I and Dicer.<xref rid="cti21067-bib-0082" ref-type="ref">82</xref>, <xref rid="cti21067-bib-0083" ref-type="ref">83</xref> TLR and RLR activation stimulates IFN‐I expression, which activates JAK‐STAT signalling to modulate expression of hundreds of IFN‐stimulated genes, thereby placing infected cells and local tissues in an antiviral state.<xref rid="cti21067-bib-0008" ref-type="ref">8</xref> Accordingly, exogenous RNAs including viral RNA, siRNA and their breakdown products are potent stimulators of IFN signalling. Such unwanted immune activation remains a significant challenge in RNA‐based therapeutics. As RNAi processing is further downregulated upon IFN stimulation,<xref rid="cti21067-bib-0084" ref-type="ref">84</xref> the IFN and RNAi systems compete in a manner detrimental to the efficacy of RNAi‐based therapeutics.</p></sec><sec id="cti21067-sec-0014"><title>Current and future therapeutic applications of RNAi</title><p>RNAi‐based approaches to antiviral therapy show both promise and new and familiar challenges. Most known primate‐infective viruses manipulate IFN signalling<xref rid="cti21067-bib-0085" ref-type="ref">85</xref>; however, despite nearly two decades of study, the role of RNAi as a specific immune defence mechanism in somatic, IFN‐responsive tissues remains controversial.<xref rid="cti21067-bib-0086" ref-type="ref">86</xref>, <xref rid="cti21067-bib-0087" ref-type="ref">87</xref> If IFN‐ and RNAi‐mediated immunity are incompatible, human‐infective viruses would likely be subjected to only weak, if any, specific RNAi‐mediated immune selective pressure. This suggests the ‘dormant’ immune functions of the mammalian RNAi system could be re‐engineered as a future antiviral or immunotherapeutic strategy. Alternatively, the gut microbiome, which is a crucial regulator of immune homeostasis, T‐cell activation and predicts treatment outcomes in anti‐PD‐1 cancer immunotherapy, might be genetically modified to secrete therapeutic small RNAs.<xref rid="cti21067-bib-0088" ref-type="ref">88</xref>, <xref rid="cti21067-bib-0089" ref-type="ref">89</xref>, <xref rid="cti21067-bib-0090" ref-type="ref">90</xref> RNAi‐based strategies could be used to modulate host immune programme or selectively and reversibly block expression of key multifunctional host proteins in or near virus‐infected tissues, thereby multiply regulating viral replication as discussed earlier.</p><p>From the first RNAi patent filing in 1998 until the end of 2017, ~ 8500 siRNA‐based and 2000 miRNA‐based therapeutic patents were filed in the United States. Most were for anticancer applications, followed by viral infections and inflammatory disorders.<xref rid="cti21067-bib-0091" ref-type="ref">91</xref> At present, the US National Library of Medicine lists 87 ‘miRNA’, 28 ‘siRNA’ and 26 ‘RNAi’ interventional clinical trials as underway or completed. Several trials involved patisiran, which, in 2018, became the first RNAi‐based therapeutic approved by the US FDA. Patisiran is an LNP‐encapsulated siRNA (siRNA‐LNP) delivered to hepatocytes, where it transiently induces RNAi‐mediated silencing of wild‐type and mutant transthyretin mRNA. Prior to infusion, patients receive a combination of oral acetaminophen, intravenous corticosteroid and histamine H1 and H2 receptor antagonists, yet infusion‐related reactions remain one of the most frequent adverse events.<xref rid="cti21067-bib-0092" ref-type="ref">92</xref> Antagonists to other immune receptors as outlined above may further suppress IFN stimulation by circulating siRNA‐LNPs or their breakdown products. Further reductions in immunogenicity may be achieved through RNA modifications such as pseudouridylation<xref rid="cti21067-bib-0093" ref-type="ref">93</xref> or by encapsulating siRNAs in exosome vesicles or other biological nanoparticles, which have the added advantage of industrial scale‐up using bioreactors.<xref rid="cti21067-bib-0094" ref-type="ref">94</xref> An alternative approach may be to again leverage the ability of viral evolution to inhibit host immunity. For example, reversibly incorporating exogenous RNA into ribonucleoprotein complexes, composed of proteins that have evolved to inhibit IFN signalling, could simultaneously yield therapeutic RNA delivery and IFN suppression.</p></sec><sec id="cti21067-sec-0015"><title>Virus‐oriented RNAi therapies</title><p>Remarkably, siRNA‐LNP ‘cocktails’ of perfect complementarity to Ebola virus (EboV) RNA have been reported to confer 100% protection in non‐human primates when administered as late as 3 days post‐lethal challenge.<xref rid="cti21067-bib-0054" ref-type="ref">54</xref> Nevertheless, nucleotide escape mutants and genetic variation between EboV strains in different geographic locations necessitate accurate, up‐to‐date sequencing data on circulating strains in order to continuously generate effective siRNA cocktails. Recently, a protocol employing the MinION portable sequencer was developed that enabled the direct sequencing of an intact RNA virus genome (IAV) for the first time.<xref rid="cti21067-bib-0095" ref-type="ref">95</xref> Direct sequencing of field EboV strains would drastically reduce the current development time of new siRNA‐LNPs. Nevertheless, further improvements in this sequencing technology will be required for accurate, cost‐effective, routine sequencing of substantially lower‐yielding and genetically diverse field strains.</p><p>As with other virus‐oriented treatments, the problem of viral resistance to RNA‐based therapeutics is perhaps best illustrated by HIV. Liu <italic>et al</italic>. produced a double long hairpin RNA (dlhRNA) that was processed endogenously to raise four anti‐HIV shRNAs directed against <italic>gag</italic>,<italic> tat</italic>,<italic> vpu</italic> and <italic>env</italic> transcripts. Despite the cells stably expressing the dlhRNA, together with the combinatorial targeting approach and using virus produced from a single molecular clone, nucleotide escape mutants emerged, integrated and proliferated in as few as 8 days post‐infection.<xref rid="cti21067-bib-0096" ref-type="ref">96</xref> Notably, however, viral transcript knockdown was variable and incomplete, thereby creating an environment suitable for escape mutant propagation. Selecting RNAi targets in the virus that are even more highly conserved, as well as incorporating a larger number of these in an shRNA ‘cocktail’, may better resist escape mutants and yield longer‐lasting efficacy in future.</p></sec><sec id="cti21067-sec-0016"><title>Host‐oriented RNAi therapies</title><p>Virus‐oriented RNA therapies engage the virus on its own terms and in full view of its evolutionary strengths. One alternative approach is to sequester host miRNAs crucial for viral replication. miR‐122 is highly expressed in liver and is necessary for HCV replication. This is targeted by two host‐oriented therapeutics, miravirsen and RG‐101.<xref rid="cti21067-bib-0097" ref-type="ref">97</xref> Miravirsen showed some efficacy with few adverse effects in clinical trials, while RG‐101 showed promising efficacy but remains subject to clinical hold because of adverse effects.</p><p>Besides safety, a clear limitation is that not all medically relevant viruses use host miRNAs as key elements in their replication strategy. One solution is to engineer such viruses to harbour endogenous miRNA‐targeting sequences. This yields recombinant viruses resembling wild‐type but with greatly reduced pathogenicity, restricted tissue tropism and impaired replicative fitness, with potential use as vaccines. Using poliovirus (PV), which replicates primarily in the pharynx and gastrointestinal tract but causes severe neurological disease, Barnes <italic>et al</italic>. first demonstrated that recombinant PV harbouring a complementary sequence of murine brain‐specific miR‐124a was severely compromised in its ability to replicate within this tissue. When this sequence was substituted for a sequence complementary to the ubiquitously expressed miRNA let‐7a, PV replication was further reduced, indicating miRNAs may be used to control tissue tropism. Notably, similar effects were obtained in mice rendered genetically unresponsive to IFN, which nevertheless generated protective antibodies against reinfection by between 10 and 10 000 times the LD<sub>50</sub> of wild‐type PV.<xref rid="cti21067-bib-0098" ref-type="ref">98</xref> This approach was recently used by Yee <italic>et al</italic>.<xref rid="cti21067-bib-0099" ref-type="ref">99</xref> towards developing a live attenuated vaccine for enterovirus 71. Similar results were also obtained by Kelly <italic>et al</italic>.<xref rid="cti21067-bib-0100" ref-type="ref">100</xref> using Coxsackievirus, where a majority of mice inoculated with recombinant virus harbouring tissue‐specific miRNA‐targeting sequences showing greatly reduced morbidity and mortality up to 70 days post‐infection. Benitez <italic>et al</italic>. showed that mice inoculated with as much as 2500 times the LD<sub>50</sub> of IAV, also modified to harbour murine miRNA‐targeting sequences, remained asymptomatic up to 10 days post‐infection. These mice were also IFN‐unresponsive, confirming that mammals can, in principle, elicit a highly effective RNAi‐mediated antiviral response and immunological memory against evolutionary diverse viruses in the absence of IFN‐I.<xref rid="cti21067-bib-0101" ref-type="ref">101</xref></p><p>Nevertheless, other viruses harbouring similar modifications have shown mixed results. In contrast to their earlier work on Coxsackievirus, Kelly <italic>et al</italic>. found vesicular stomatitis virus engineered to contain various host miRNA‐targeting sequences largely resisted miRNA‐mediated restriction. Nevertheless, a decrease in neurotoxicity was observed with miR‐125 that also preserved the virus’ oncolytic activity,<xref rid="cti21067-bib-0102" ref-type="ref">102</xref> properties that are crucial in cancer immunotherapy applications. DenV was successfully restricted from hematopoietic cells by introducing four miR‐142 targeting sites, although the virus quickly reverted and continued proliferating at low levels after excising all four sites.<xref rid="cti21067-bib-0103" ref-type="ref">103</xref> Since there appears to be no clear pattern that might explain these disparate effects between virus species, additional work remains in order to use recombinant miR‐targeting viruses for routine therapeutic use.</p><p>Nearly 20 years elapsed between the first patent filings and the realisation of an approved RNAi‐based therapeutic. While challenges remain, the coming decade appears likely to mark the beginning of the growth curve for creative new approaches to RNA‐based therapeutics for antiviral and immunotherapeutic applications.</p></sec></sec><sec id="cti21067-sec-0017"><title>Designer vaccines</title><p>To elicit humoral as well as long‐lasting cellular immunity, live attenuated vaccines are the most effective therapy currently available. These are typically produced by passaging viral isolates in permissive immune‐deficient hosts such as embryonated chicken eggs or non‐human continuous cell lines (e.g. Vero), thereby forcing viral re‐adaptation and loss of virulence in the original host. However, the basis for attenuation is usually ill‐defined. Some species or clinical isolates are not readily amenable to current <italic>in vitro</italic> culturing methods (e.g. norovirus),<xref rid="cti21067-bib-0104" ref-type="ref">104</xref> which often fail to recapitulate essential elements of the viral replication cycle and pathogenesis. Furthermore, attenuated strains are often so compromised that immune adjuvants are required to stimulate antigenicity upon inoculation. Collectively, these challenges increase production costs of many vaccines while limiting detailed studies and the number of viruses for which safe and effective live vaccines can be produced.</p><p>To address production costs, RNAi and CRISPR/Cas9 have recently been applied in attempts to engineer cells that produce greater viral yields. Using a genome‐wide RNAi screen in HEp‐2C cells and validation in the Vero cell line approved for vaccine development, van der Sanden <italic>et al</italic>. identified several gene knockdowns that drastically increased yields of multiple PV, enterovirus and rotavirus strains. However, these effects on viral replication were not recapitulated on follow‐up.<xref rid="cti21067-bib-0105" ref-type="ref">105</xref> As the reasons for these discrepant results remain unclear, challenges evidently remain in engineering cell lines that support greater viral yields for vaccine deployment.</p><p>An alternative approach is to genetically re‐program cells derived from the host species that serve as the natural reservoir of the virus. One advantage of this approach is the likely greater amenability of previously uncultivable or poor‐yielding viruses for cultivation <italic>ex vivo</italic>. Additionally, the resulting strain will likely preserve some replicative competence upon inoculation, thereby eliciting stronger immunity in the absence of adjuvants. The challenge remains, however, to identify which parts of the cell or culture methods should be modified to generate broad permissiveness, high titres and greatly reduced virulence simultaneously. Obvious candidates include genes that restrict viral replication but are dispensable for cell survival, such as IFN genes and their signalling components, and potentially certain multifunctional proteins. Taken to its logical conclusion, it should be possible to genetically engineer an immune‐null human cell substrate within which to passage virus free of virulence factor targets and immune selective pressure. In this way, the strain that emerges will likely exhibit strong antigenicity but severe degradation in mechanisms of host immune antagonism. Such an approach may also prove useful in the context of viruses that cause severe disease primarily through cytokine hyperactivation.</p><p>Additional modifications to this host‐oriented approach may further improve vaccine yield or safety. These may include eliminating pro‐apoptotic genes to limit virus‐induced programmed cell death and increase viral titres. The culture system itself may be improved to better represent the three‐dimensional microarchitecture of the host tissue and other features necessary for efficient viral replication. Organoids and other stem cell‐derived tissues represent one approach under recent and intensifying examination. Human lung organoids have been demonstrated to recapitulate key properties of RSV pathogenesis,<xref rid="cti21067-bib-0106" ref-type="ref">106</xref> and human intestinal epithelium has been developed for previously uncultivable norovirus.<xref rid="cti21067-bib-0104" ref-type="ref">104</xref> Additionally, incorporating multiple tissue‐specific miRNA‐targeting sequences within the attenuated viral genome may improve vaccine safety by impairing its ability to replicate within inflammation‐sensitive or irreplaceable tissues. Inversely, this same strategy may be used to help guide infection of certain tissues such as oncolytic viruses in the case of cancer immunotherapy.<xref rid="cti21067-bib-0100" ref-type="ref">100</xref> Another safety feature could involve a drug‐selective ‘kill switch’, whereby key viral proteins are fused to the FK506‐binding protein 12 destabilisation domain. Viral fusion proteins are ‘rescued’ from proteasomal degradation in the presence of the drug Shield‐1 but efficiently degraded upon its removal,<xref rid="cti21067-bib-0107" ref-type="ref">107</xref> thereby yielding a conditionally replication‐incompetent strain. The coming decade appears likely to see two key transitions: from empirical to designer vaccines, and from viruses as pathogens to important tools in biotechnology.</p></sec><sec id="cti21067-sec-0018"><title>Neo‐virology and future biotechnologies</title><p>Of the 8.7 million known species on earth, viruses are likely the most ancient and prolific with at least 10<sup>31</sup> virions estimated to exist today.<xref rid="cti21067-bib-0010" ref-type="ref">10</xref> Sampling only a fraction of these diverse host–virus interactions has already resulted in ground‐breaking biotechnologies including biomolecule and bioactive compound delivery systems, RNAi‐mediated antiviral therapies and genetic engineering using zinc finger nucleases, TALENs and CRISPR/Cas9. These have wide‐ranging applications in antiviral therapy and vaccine development, immunotherapy, regenerative medicine, environmental science and numerous other fields.</p><p>Neo‐virology is an emerging field aiming to further this trajectory of innovation by systematically characterising the roles of viruses and viral‐mediated processes in the entire living biosphere.<xref rid="cti21067-bib-0010" ref-type="ref">10</xref> As the unexplored genetic diversity of viruses is unlocked through improvements in sequencing technologies and big data analysis, the molecular basis of host–virus interactions and the evolutionary relationships between highly divergent species are becoming clearer.</p><p>One area of interest is the increasing number of nucleocytoplasmic large DNA viruses (NCLDVs) being discovered in prokaryote, protist and invertebrate hosts and in soil and water. These include two amoebal pathogens: pandoravirus, which harbours the largest known viral genome at 2.5 Mb,<xref rid="cti21067-bib-0108" ref-type="ref">108</xref> and mimivirus, an emerging human pathogen harbouring a 1.2 Mb genome.<xref rid="cti21067-bib-0109" ref-type="ref">109</xref> In stark contrast to RNA viruses, these giant DNA viruses appear capable of acquiring additional information without clear bound, presenting an alternative solution to the information economy paradox. These viruses are also suggested to readily generate genes <italic>de novo</italic>.<xref rid="cti21067-bib-0013" ref-type="ref">13</xref> While few complete genome sequences of such viruses are currently available, most of the numerous proteins encoded by these vast viral genomes are entirely novel.<xref rid="cti21067-bib-0108" ref-type="ref">108</xref>, <xref rid="cti21067-bib-0110" ref-type="ref">110</xref>, <xref rid="cti21067-bib-0111" ref-type="ref">111</xref> If the process for <italic>de novo</italic> generation of viral genes can be harnessed, this could support efforts at directed evolution of new and useful biological functions.</p><p>Nucleocytoplasmic large DNA viruses proteins with inferred functions reveal interesting patterns. A recently discovered NCLDV encodes a full set of eukaryote‐like histones and a DNA polymerase, potentially placing it at the root of the eukaryotic clades.<xref rid="cti21067-bib-0110" ref-type="ref">110</xref> An ancient NCLDV‐like virus may have been responsible for the origin of the eukaryote nucleus itself.<xref rid="cti21067-bib-0112" ref-type="ref">112</xref> Subsequently, eukaryote multicellularity, coupled with programmed cell death, may have emerged as an ancient antiviral defence mechanism,<xref rid="cti21067-bib-0113" ref-type="ref">113</xref> possibly enabling the rise of complex life. Retroviral elements, in addition to driving formation of the mammalian placenta, control hormones involved in gestation and birth timing in some mammals.<xref rid="cti21067-bib-0114" ref-type="ref">114</xref> Such elements comprise ~ 8% of the human genome, which also contains genetic material derived from viruses with no retro‐transcription or integration functionality.<xref rid="cti21067-bib-0115" ref-type="ref">115</xref> Thus, despite being strictly non‐living, viruses have radically shaped the living biosphere. Understanding these processes could enable new approaches to control the basic functions of life.</p><p>Areas where improved understanding of such host–virus interactions could have immediate implications include human disease, bioremediation of harmful algal blooms and climate change. Contemporary viruses overwhelmingly infect marine microorganisms, turning over an estimated 20% of the ocean microbiome daily.<xref rid="cti21067-bib-0009" ref-type="ref">9</xref> These infections have significant effects on carbon absorption by oceans as well as global nutrient and energy cycles.<xref rid="cti21067-bib-0011" ref-type="ref">11</xref>, <xref rid="cti21067-bib-0014" ref-type="ref">14</xref> Nevertheless, the interactions between the ocean virome and microbiome and their effects climate remain poorly characterised. By examining evolutionarily diverse host–virus interactions in detail, immunology and virology may provide effective solutions to not only human disease but also cost, environmental and other sustainability issues of our time.</p></sec></sec><sec id="cti21067-sec-0019"><title>Concluding remarks</title><p>As outlined in this review, current antivirals almost exclusively target virus proteins and have significant development costs, limited therapeutic range and are ultimately susceptible to escape mutant selection. Despite being intractably limited in informational size, RNA viruses are thorough problem solvers, often subverting multitasking host proteins to achieve favorable host subversion at minimal informational cost. Such solutions to the viral information economy paradox are often conserved, creating opportunities to leverage imbricated multidependency on key host proteins for host‐oriented antiviral therapies that are more effective, broad‐acting and ultimately more cost‐effective. Although such proteins can present challenging therapeutic targets, host‐oriented therapies will synergise with increased therapeutic drug availability and developments in RNAi, precision medicine and immunotherapy. Additionally, methods of increasing viral antigenicity yet controlling replication and tissue tropism will increase the number of viruses for which safe and highly effective vaccines can be produced. Viruses such as NCLDVs appear to readily acquire new information with which to subvert their hosts. The fruits of problem‐solving by such viruses include large numbers of proteins with unique and unknown biological functions. The influence and genetic hallmarks of viruses at both extremes are found in humans and throughout the living biosphere. By expanding the examination of evolutionarily diverse host–virus interactions, disease, cost, environmental and other sustainability issues of our time may be remedied by leveraging, rather than yielding to, the properties of RNA and DNA viruses as developed through co‐evolution with their hosts.</p></sec><sec sec-type="COI-statement" id="cti21067-sec-0020"><title>Conflict of interest</title><p>The author declares no conflict of interest.</p></sec><sec sec-type="supplementary-material"><title>Supporting information</title><supplementary-material content-type="local-data" id="cti21067-sup-0001"><caption><p> </p></caption><media xlink:href="CTI2-8-e1067-s001.xlsx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material></sec></body><back><ref-list content-type="cited-references" id="cti21067-bibl-0001"><title>References</title><ref id="cti21067-bib-0001"><label>1</label><mixed-citation publication-type="journal" id="cti21067-cit-0001"><string-name><surname>Woolhouse</surname><given-names>MEJ</given-names></string-name>, <string-name><surname>Brierley</surname><given-names>L</given-names></string-name>. <article-title>Epidemiological characteristics of human‐infective RNA viruses</article-title>. <source xml:lang="en">Sci Data</source><year>2018</year>; 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