Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection
Identifieur interne : 001440 ( Pmc/Curation ); précédent : 001439; suivant : 001441Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection
Auteurs : Emmie De Wit ; Friederike Feldmann ; Jacqueline Cronin ; Robert Jordan ; Atsushi Okumura ; Tina Thomas ; Dana Scott ; Tomas Cihlar ; Heinz FeldmannSource :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2020.
Abstract
Middle East Respiratory Syndrome, caused by the MERS coronavirus (MERS-CoV), continues to cause severe respiratory disease with a high case fatality rate. To date, potential antiviral treatments for MERS-CoV have shown limited efficacy in animal studies. Here, we tested the efficacy of the broad-acting antiviral remdesivir in the rhesus macaque model of MERS-CoV infection. Remdesivir reduced the severity of disease, virus replication, and damage to the lungs when administered either before or after animals were infected with MERS-CoV. Our data show that remdesivir is a promising antiviral treatment against MERS that could be considered for implementation in clinical trials. It may also have utility for related coronaviruses such as the novel coronavirus 2019-nCoV emerging from Wuhan, China.
Url:
DOI: 10.1073/pnas.1922083117
PubMed: 32054787
PubMed Central: 7104368
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first="Jacqueline" last="Cronin">Jacqueline Cronin</name><affiliation><nlm:aff id="aff1">Laboratory of Virology, National Institute of Allergy and Infectious Diseases,<institution>NIH</institution>, Hamilton,<addr-line>MT</addr-line> 59840;</nlm:aff></affiliation></author><author><name sortKey="Jordan, Robert" sort="Jordan, Robert" uniqKey="Jordan R" first="Robert" last="Jordan">Robert Jordan</name><affiliation><nlm:aff id="aff3">Biology Department,<institution>Gilead Sciences</institution>, Foster City,<addr-line>CA</addr-line> 94404;</nlm:aff></affiliation></author><author><name sortKey="Okumura, Atsushi" sort="Okumura, Atsushi" uniqKey="Okumura A" first="Atsushi" last="Okumura">Atsushi Okumura</name><affiliation><nlm:aff id="aff4">Center for Infection and Immunity, Mailman School of Public Health,<institution>Columbia University</institution>, New York,<addr-line>NY</addr-line> 10032</nlm:aff></affiliation></author><author><name sortKey="Thomas, Tina" sort="Thomas, Tina" 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remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection</title><author><name sortKey="De Wit, Emmie" sort="De Wit, Emmie" uniqKey="De Wit E" first="Emmie" last="De Wit">Emmie De Wit</name><affiliation><nlm:aff id="aff1">Laboratory of Virology, National Institute of Allergy and Infectious Diseases,<institution>NIH</institution>, Hamilton,<addr-line>MT</addr-line> 59840;</nlm:aff></affiliation></author><author><name sortKey="Feldmann, Friederike" sort="Feldmann, Friederike" uniqKey="Feldmann F" first="Friederike" last="Feldmann">Friederike Feldmann</name><affiliation><nlm:aff id="aff2">Rocky Mountain Veterinary Branch, National Institute of Allergy and Infectious Diseases,<institution>NIH</institution>, Hamilton,<addr-line>MT</addr-line> 59840;</nlm:aff></affiliation></author><author><name sortKey="Cronin, Jacqueline" sort="Cronin, Jacqueline" uniqKey="Cronin J" first="Jacqueline" last="Cronin">Jacqueline Cronin</name><affiliation><nlm:aff id="aff1">Laboratory of Virology, National Institute of Allergy and Infectious Diseases,<institution>NIH</institution>, Hamilton,<addr-line>MT</addr-line> 59840;</nlm:aff></affiliation></author><author><name sortKey="Jordan, Robert" sort="Jordan, Robert" uniqKey="Jordan R" first="Robert" last="Jordan">Robert Jordan</name><affiliation><nlm:aff id="aff3">Biology Department,<institution>Gilead Sciences</institution>, Foster City,<addr-line>CA</addr-line> 94404;</nlm:aff></affiliation></author><author><name sortKey="Okumura, Atsushi" sort="Okumura, Atsushi" uniqKey="Okumura A" first="Atsushi" last="Okumura">Atsushi Okumura</name><affiliation><nlm:aff id="aff4">Center for Infection and Immunity, Mailman School of Public Health,<institution>Columbia University</institution>, New York,<addr-line>NY</addr-line> 10032</nlm:aff></affiliation></author><author><name sortKey="Thomas, Tina" sort="Thomas, Tina" uniqKey="Thomas T" first="Tina" last="Thomas">Tina Thomas</name><affiliation><nlm:aff id="aff1">Laboratory of Virology, National Institute of Allergy and Infectious Diseases,<institution>NIH</institution>, Hamilton,<addr-line>MT</addr-line> 59840;</nlm:aff></affiliation></author><author><name sortKey="Scott, Dana" sort="Scott, Dana" uniqKey="Scott D" first="Dana" last="Scott">Dana Scott</name><affiliation><nlm:aff id="aff2">Rocky Mountain Veterinary Branch, National Institute of Allergy and Infectious Diseases,<institution>NIH</institution>, Hamilton,<addr-line>MT</addr-line> 59840;</nlm:aff></affiliation></author><author><name sortKey="Cihlar, Tomas" sort="Cihlar, Tomas" uniqKey="Cihlar T" first="Tomas" last="Cihlar">Tomas Cihlar</name><affiliation><nlm:aff id="aff3">Biology Department,<institution>Gilead Sciences</institution>, Foster City,<addr-line>CA</addr-line> 94404;</nlm:aff></affiliation></author><author><name sortKey="Feldmann, Heinz" sort="Feldmann, Heinz" uniqKey="Feldmann H" first="Heinz" last="Feldmann">Heinz Feldmann</name><affiliation><nlm:aff id="aff1">Laboratory of Virology, National Institute of Allergy and Infectious Diseases,<institution>NIH</institution>, Hamilton,<addr-line>MT</addr-line> 59840;</nlm:aff></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Significance</title><p>Middle East Respiratory Syndrome, caused by the MERS coronavirus (MERS-CoV), continues to cause severe respiratory disease with a high case fatality rate. To date, potential antiviral treatments for MERS-CoV have shown limited efficacy in animal studies. Here, we tested the efficacy of the broad-acting antiviral remdesivir in the rhesus macaque model of MERS-CoV infection. Remdesivir reduced the severity of disease, virus replication, and damage to the lungs when administered either before or after animals were infected with MERS-CoV. Our data show that remdesivir is a promising antiviral treatment against MERS that could be considered for implementation in clinical trials. It may also have utility for related coronaviruses such as the novel coronavirus 2019-nCoV emerging from Wuhan, China.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Modjarrad, K" uniqKey="Modjarrad K">K. Modjarrad</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brende, B" uniqKey="Brende B">B. Brende</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lo, M K" uniqKey="Lo M">M. K. Lo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Warren, T K" uniqKey="Warren T">T. K. Warren</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lo, M K" uniqKey="Lo M">M. K. Lo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sheahan, T P" uniqKey="Sheahan T">T. P. Sheahan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sheahan, T P" uniqKey="Sheahan T">T. P. Sheahan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Agostini, M L" uniqKey="Agostini M">M. L. Agostini</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De Wit, E" uniqKey="De Wit E">E. de Wit</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hui, D S" uniqKey="Hui D">D. S. Hui</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Assiri, A" uniqKey="Assiri A">A. Assiri</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chan, J F" uniqKey="Chan J">J. F. Chan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, Z" uniqKey="Chen Z">Z. Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De Wit, E" uniqKey="De Wit E">E. de Wit</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Falzarano, D" uniqKey="Falzarano D">D. Falzarano</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Doremalen, N" uniqKey="Van Doremalen N">N. van Doremalen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Al Abdely, H M" uniqKey="Al Abdely H">H. M. Al-Abdely</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bin, S Y" uniqKey="Bin S">S. Y. Bin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Prescott, J" uniqKey="Prescott J">J. Prescott</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dornemann, J" uniqKey="Dornemann J">J. Dörnemann</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jacobs, M" uniqKey="Jacobs M">M. Jacobs</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mulangu, S" uniqKey="Mulangu S">S. Mulangu</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Falzarano, D" uniqKey="Falzarano D">D. Falzarano</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brining, D L" uniqKey="Brining D">D. L. Brining</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Corman, V M" uniqKey="Corman V">V. M. Corman</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="iso-abbrev">Proc. Natl. Acad. Sci. U.S.A</journal-id><journal-id journal-id-type="hwp">pnas</journal-id><journal-id journal-id-type="pmc">pnas</journal-id><journal-id journal-id-type="publisher-id">PNAS</journal-id><journal-title-group><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title></journal-title-group><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">32054787</article-id><article-id pub-id-type="pmc">7104368</article-id><article-id pub-id-type="publisher-id">201922083</article-id><article-id pub-id-type="doi">10.1073/pnas.1922083117</article-id><article-categories><subj-group subj-group-type="hwp-journal-coll"><subject>530</subject></subj-group><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Microbiology</subject></subj-group></subj-group></article-categories><title-group><article-title>Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection</article-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0002-9763-7758</contrib-id><name><surname>de Wit</surname><given-names>Emmie</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="corresp" rid="cor1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Feldmann</surname><given-names>Friederike</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cronin</surname><given-names>Jacqueline</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jordan</surname><given-names>Robert</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Okumura</surname><given-names>Atsushi</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Thomas</surname><given-names>Tina</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Scott</surname><given-names>Dana</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cihlar</surname><given-names>Tomas</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Feldmann</surname><given-names>Heinz</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><aff id="aff1"><sup>a</sup>Laboratory of Virology, National Institute of Allergy and Infectious Diseases,<institution>NIH</institution>, Hamilton,<addr-line>MT</addr-line> 59840;</aff><aff id="aff2"><sup>b</sup>Rocky Mountain Veterinary Branch, National Institute of Allergy and Infectious Diseases,<institution>NIH</institution>, Hamilton,<addr-line>MT</addr-line> 59840;</aff><aff id="aff3"><sup>c</sup>Biology Department,<institution>Gilead Sciences</institution>, Foster City,<addr-line>CA</addr-line> 94404;</aff><aff id="aff4"><sup>d</sup>Center for Infection and Immunity, Mailman School of Public Health,<institution>Columbia University</institution>, New York,<addr-line>NY</addr-line> 10032</aff></contrib-group><author-notes><corresp id="cor1"><sup>1</sup>To whom correspondence may be addressed. Email: <email>Emmie.deWit@nih.gov</email>.</corresp><fn fn-type="edited-by"><p>Edited by Michael B. A. Oldstone, Scripps Research Institute, La Jolla, CA, and approved February 7, 2020 (received for review December 16, 2019)</p></fn><fn fn-type="con"><p>Author contributions: E.d.W., R.J., and H.F. designed research; E.d.W., F.F., J.C., A.O., T.T., and D.S. performed research; T.C. contributed new reagents/analytic tools; E.d.W., A.O., and D.S. analyzed data; E.d.W. and H.F. wrote the paper; and F.F., J.C., R.J., A.O., T.T., D.S., and T.C. read and approved the manuscript.</p></fn></author-notes><pub-date pub-type="ppub"><day>24</day><month>3</month><year>2020</year></pub-date><pub-date pub-type="epub"><day>13</day><month>2</month><year>2020</year></pub-date><pub-date pub-type="pmc-release"><day>13</day><month>2</month><year>2020</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>117</volume><issue>12</issue><fpage>6771</fpage><lpage>6776</lpage><permissions><copyright-statement>Copyright © 2020 the Author(s). Published by PNAS.</copyright-statement><copyright-year>2020</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><ali:license_ref specific-use="vor">https://creativecommons.org/licenses/by/4.0/</ali:license_ref><license-p>This open access article is distributed under <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License 4.0 (CC BY)</ext-link>.</license-p></license></permissions><self-uri xlink:title="pdf" xlink:href="pnas.201922083.pdf"></self-uri><abstract abstract-type="executive-summary"><title>Significance</title><p>Middle East Respiratory Syndrome, caused by the MERS coronavirus (MERS-CoV), continues to cause severe respiratory disease with a high case fatality rate. To date, potential antiviral treatments for MERS-CoV have shown limited efficacy in animal studies. Here, we tested the efficacy of the broad-acting antiviral remdesivir in the rhesus macaque model of MERS-CoV infection. Remdesivir reduced the severity of disease, virus replication, and damage to the lungs when administered either before or after animals were infected with MERS-CoV. Our data show that remdesivir is a promising antiviral treatment against MERS that could be considered for implementation in clinical trials. It may also have utility for related coronaviruses such as the novel coronavirus 2019-nCoV emerging from Wuhan, China.</p></abstract><abstract><p>The continued emergence of Middle East Respiratory Syndrome (MERS) cases with a high case fatality rate stresses the need for the availability of effective antiviral treatments. Remdesivir (GS-5734) effectively inhibited MERS coronavirus (MERS-CoV) replication in vitro, and showed efficacy against Severe Acute Respiratory Syndrome (SARS)-CoV in a mouse model. Here, we tested the efficacy of prophylactic and therapeutic remdesivir treatment in a nonhuman primate model of MERS-CoV infection, the rhesus macaque. Prophylactic remdesivir treatment initiated 24 h prior to inoculation completely prevented MERS-CoV−induced clinical disease, strongly inhibited MERS-CoV replication in respiratory tissues, and prevented the formation of lung lesions. Therapeutic remdesivir treatment initiated 12 h postinoculation also provided a clear clinical benefit, with a reduction in clinical signs, reduced virus replication in the lungs, and decreased presence and severity of lung lesions. The data presented here support testing of the efficacy of remdesivir treatment in the context of a MERS clinical trial. It may also be considered for a wider range of coronaviruses, including the currently emerging novel coronavirus 2019-nCoV.</p></abstract><kwd-group><kwd>MERS-CoV</kwd><kwd>antiviral</kwd><kwd>animal model</kwd><kwd>remdesivir</kwd><kwd>therapy</kwd></kwd-group><funding-group><award-group id="gs1"><funding-source id="sp1">Division of Intramural Research, National Institute of Allergy and Infectious Diseases (DIR, NIAID)<named-content content-type="funder-id">100006492</named-content></funding-source><award-id rid="sp1">N/A</award-id><principal-award-recipient>Emmie De Wit</principal-award-recipient><principal-award-recipient>Friederike Feldmann</principal-award-recipient><principal-award-recipient>Jacqueline Cronin</principal-award-recipient><principal-award-recipient>Robert Jordan</principal-award-recipient><principal-award-recipient>Atsushi Okumura</principal-award-recipient><principal-award-recipient>Tina Thomas</principal-award-recipient><principal-award-recipient>Dana P. Scott</principal-award-recipient><principal-award-recipient>Tomas Cihlar</principal-award-recipient><principal-award-recipient>Heinz Feldmann</principal-award-recipient></award-group></funding-group><counts><page-count count="6"></page-count></counts><custom-meta-group><custom-meta><meta-name>access-type</meta-name><meta-value>free</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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