Activity of and Effect of Subcutaneous Treatment with the Broad-Spectrum Antiviral Lectin Griffithsin in Two Laboratory Rodent Models
Identifieur interne : 001795 ( Main/Exploration ); précédent : 001794; suivant : 001796Activity of and Effect of Subcutaneous Treatment with the Broad-Spectrum Antiviral Lectin Griffithsin in Two Laboratory Rodent Models
Auteurs : Christopher Barton [États-Unis] ; J. Calvin Kouokam [États-Unis] ; Amanda B. Lasnik [États-Unis] ; Oded Foreman [États-Unis] ; Alexander Cambon [États-Unis] ; Guy Brock [États-Unis] ; David C. Montefiori [États-Unis] ; Fakhrieh Vojdani [États-Unis] ; Alison A. Mccormick [États-Unis] ; Barry R. O'Keefe [États-Unis] ; Kenneth E. Palmer [États-Unis]Source :
- Antimicrobial agents and chemotherapy [ 0066-4804 ] ; 2014.
Descripteurs français
- Pascal (Inist)
English descriptors
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Abstract
Griffithsin (GRFT) is a red-alga-derived lectin that binds the terminal mannose residues of N-linked glycans found on the surface of human immunodeficiency virus type 1 (HIV-1), HIV-2, and other enveloped viruses, including hepatitis C virus (HCV), severe acute respiratory syndrome coronavirus (SARS-CoV), and Ebola virus. GRFT displays no human T-cell mitogenic activity and does not induce production of proinflammatory cytokines in treated human cell lines. However, despite the growing evidence showing the broad-spectrum nanomolar or better antiviral activity of GRFT, no study has reported a comprehensive assessment of GRFT safety as a potential systemic antiviral treatment. The results presented in this work show that minimal toxicity was induced by a range of single and repeated daily subcutaneous doses of GRFT in two rodent species, although we noted treatment-associated increases in spleen and liver mass suggestive of an antidrug immune response. The drug is systemically distributed, accumulating to high levels in the serum and plasma after subcutaneous delivery. Further, we showed that serum from GRFT-treated animals retained antiviral activity against HIV-1-enveloped pseudoviruses in a cell-based neutralization assay. Overall, our data presented here show that GRFT accumulates to relevant therapeutic concentrations which are tolerated with minimal toxicity. These studies support further development of GRFT as a systemic antiviral therapeutic agent against enveloped viruses, although deimmunizing the molecule may be necessary if it is to be used in long-term treatment of chronic viral infections.
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Calvin" last="Kouokam">J. Calvin Kouokam</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, University of Louisville School of Medicine</s1><s2>Louisville, Kentucky</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Kentucky</region></placeName></affiliation><affiliation wicri:level="2"><inist:fA14 i1="02"><s1>Owensboro Cancer Research Program</s1><s2>Owensboro, Kentucky</s2><s3>USA</s3><sZ>2 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Kentucky</region></placeName></affiliation></author><author><name sortKey="Lasnik, Amanda B" sort="Lasnik, Amanda B" uniqKey="Lasnik A" first="Amanda B." last="Lasnik">Amanda B. Lasnik</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, University of Louisville School of Medicine</s1><s2>Louisville, Kentucky</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Kentucky</region></placeName></affiliation></author><author><name sortKey="Foreman, Oded" sort="Foreman, Oded" uniqKey="Foreman O" first="Oded" last="Foreman">Oded Foreman</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Jackson Laboratory</s1><s2>Bar Harbor, Maine</s2><s3>USA</s3><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maine (État)</region></placeName></affiliation></author><author><name sortKey="Cambon, Alexander" sort="Cambon, Alexander" uniqKey="Cambon A" first="Alexander" last="Cambon">Alexander Cambon</name><affiliation wicri:level="2"><inist:fA14 i1="04"><s1>Department of Bioinformatics and Biostatistics, University of Louisville</s1><s2>Louisville, Kentucky</s2><s3>USA</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Kentucky</region></placeName></affiliation></author><author><name sortKey="Brock, Guy" sort="Brock, Guy" uniqKey="Brock G" first="Guy" last="Brock">Guy Brock</name><affiliation wicri:level="2"><inist:fA14 i1="04"><s1>Department of Bioinformatics and Biostatistics, University of Louisville</s1><s2>Louisville, Kentucky</s2><s3>USA</s3><sZ>5 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Kentucky</region></placeName></affiliation></author><author><name sortKey="Montefiori, David C" sort="Montefiori, David C" uniqKey="Montefiori D" first="David C." last="Montefiori">David C. Montefiori</name><affiliation wicri:level="2"><inist:fA14 i1="05"><s1>Department of Surgery, Duke University School of Medicine</s1><s2>Durham, North Carolina</s2><s3>USA</s3><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Vojdani, Fakhrieh" sort="Vojdani, Fakhrieh" uniqKey="Vojdani F" first="Fakhrieh" last="Vojdani">Fakhrieh Vojdani</name><affiliation wicri:level="2"><inist:fA14 i1="06"><s1>Intrucept Biomedicine LLC</s1><s2>Owensboro, Kentucky</s2><s3>USA</s3><sZ>8 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Kentucky</region></placeName></affiliation></author><author><name sortKey="Mccormick, Alison A" sort="Mccormick, Alison A" uniqKey="Mccormick A" first="Alison A." last="Mccormick">Alison A. Mccormick</name><affiliation wicri:level="2"><inist:fA14 i1="07"><s1>Touro College of Pharmacy</s1><s2>Vallejo, California</s2><s3>USA</s3><sZ>9 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="O Keefe, Barry R" sort="O Keefe, Barry R" uniqKey="O Keefe B" first="Barry R." last="O'Keefe">Barry R. O'Keefe</name><affiliation wicri:level="2"><inist:fA14 i1="08"><s1>National Cancer Institute</s1><s2>Frederick, Maryland</s2><s3>USA</s3><sZ>10 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Palmer, Kenneth E" sort="Palmer, Kenneth E" uniqKey="Palmer K" first="Kenneth E." last="Palmer">Kenneth E. Palmer</name><affiliation wicri:level="2"><inist:fA14 i1="01"><s1>Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, University of Louisville School of Medicine</s1><s2>Louisville, Kentucky</s2><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Kentucky</region></placeName></affiliation><affiliation wicri:level="2"><inist:fA14 i1="02"><s1>Owensboro Cancer Research Program</s1><s2>Owensboro, Kentucky</s2><s3>USA</s3><sZ>2 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Kentucky</region></placeName></affiliation><affiliation wicri:level="2"><inist:fA14 i1="06"><s1>Intrucept Biomedicine LLC</s1><s2>Owensboro, Kentucky</s2><s3>USA</s3><sZ>8 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Kentucky</region></placeName></affiliation></author></analytic><series><title level="j" type="main">Antimicrobial agents and chemotherapy</title><title level="j" type="abbreviated">Antimicrob. agents chemother.</title><idno type="ISSN">0066-4804</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Antimicrobial agents and chemotherapy</title><title level="j" type="abbreviated">Antimicrob. agents chemother.</title><idno type="ISSN">0066-4804</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animal model</term><term>Antiviral</term><term>Biological activity</term><term>Griffithsin</term><term>Laboratory</term><term>Lectin</term><term>Spectrum</term><term>Subcutaneous</term><term>Subcutaneous administration</term><term>Treatment</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Activité biologique</term><term>Voie souscutanée</term><term>Souscutané</term><term>Traitement</term><term>Spectre</term><term>Antiviral</term><term>Lectine</term><term>Laboratoire</term><term>Modèle animal</term><term>Griffithsine</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Griffithsin (GRFT) is a red-alga-derived lectin that binds the terminal mannose residues of N-linked glycans found on the surface of human immunodeficiency virus type 1 (HIV-1), HIV-2, and other enveloped viruses, including hepatitis C virus (HCV), severe acute respiratory syndrome coronavirus (SARS-CoV), and Ebola virus. GRFT displays no human T-cell mitogenic activity and does not induce production of proinflammatory cytokines in treated human cell lines. However, despite the growing evidence showing the broad-spectrum nanomolar or better antiviral activity of GRFT, no study has reported a comprehensive assessment of GRFT safety as a potential systemic antiviral treatment. The results presented in this work show that minimal toxicity was induced by a range of single and repeated daily subcutaneous doses of GRFT in two rodent species, although we noted treatment-associated increases in spleen and liver mass suggestive of an antidrug immune response. The drug is systemically distributed, accumulating to high levels in the serum and plasma after subcutaneous delivery. Further, we showed that serum from GRFT-treated animals retained antiviral activity against HIV-1-enveloped pseudoviruses in a cell-based neutralization assay. Overall, our data presented here show that GRFT accumulates to relevant therapeutic concentrations which are tolerated with minimal toxicity. These studies support further development of GRFT as a systemic antiviral therapeutic agent against enveloped viruses, although deimmunizing the molecule may be necessary if it is to be used in long-term treatment of chronic viral infections.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Californie</li><li>Caroline du Nord</li><li>Kentucky</li><li>Maine (État)</li><li>Maryland</li></region></list><tree><country name="États-Unis"><region name="Kentucky"><name sortKey="Barton, Christopher" sort="Barton, Christopher" uniqKey="Barton C" first="Christopher" last="Barton">Christopher Barton</name></region><name sortKey="Brock, Guy" sort="Brock, Guy" uniqKey="Brock G" first="Guy" last="Brock">Guy Brock</name><name sortKey="Cambon, Alexander" sort="Cambon, Alexander" uniqKey="Cambon A" first="Alexander" last="Cambon">Alexander Cambon</name><name sortKey="Foreman, Oded" sort="Foreman, Oded" uniqKey="Foreman O" first="Oded" last="Foreman">Oded Foreman</name><name sortKey="Kouokam, J Calvin" sort="Kouokam, J Calvin" uniqKey="Kouokam J" first="J. Calvin" last="Kouokam">J. Calvin Kouokam</name><name sortKey="Kouokam, J Calvin" sort="Kouokam, J Calvin" uniqKey="Kouokam J" first="J. Calvin" last="Kouokam">J. Calvin Kouokam</name><name sortKey="Lasnik, Amanda B" sort="Lasnik, Amanda B" uniqKey="Lasnik A" first="Amanda B." last="Lasnik">Amanda B. Lasnik</name><name sortKey="Mccormick, Alison A" sort="Mccormick, Alison A" uniqKey="Mccormick A" first="Alison A." last="Mccormick">Alison A. Mccormick</name><name sortKey="Montefiori, David C" sort="Montefiori, David C" uniqKey="Montefiori D" first="David C." last="Montefiori">David C. Montefiori</name><name sortKey="O Keefe, Barry R" sort="O Keefe, Barry R" uniqKey="O Keefe B" first="Barry R." last="O'Keefe">Barry R. O'Keefe</name><name sortKey="Palmer, Kenneth E" sort="Palmer, Kenneth E" uniqKey="Palmer K" first="Kenneth E." last="Palmer">Kenneth E. Palmer</name><name sortKey="Palmer, Kenneth E" sort="Palmer, Kenneth E" uniqKey="Palmer K" first="Kenneth E." last="Palmer">Kenneth E. Palmer</name><name sortKey="Palmer, Kenneth E" sort="Palmer, Kenneth E" uniqKey="Palmer K" first="Kenneth E." last="Palmer">Kenneth E. Palmer</name><name sortKey="Vojdani, Fakhrieh" sort="Vojdani, Fakhrieh" uniqKey="Vojdani F" first="Fakhrieh" last="Vojdani">Fakhrieh Vojdani</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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