1887

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Volume 96, Issue 12

Chloroquine inhibited Ebola virus replication but failed to protect against infection and disease in the guinea pig model Open Access

Abstract

Ebola virus (EBOV) is highly pathogenic, with a predisposition to cause outbreaks in human populations accompanied by significant mortality. Owing to the lack of approved therapies, screening programmes of potentially efficacious drugs have been undertaken. One of these studies has demonstrated the possible utility of chloroquine against EBOV using pseudotyped assays. In mouse models of EBOV disease there are conflicting reports of the therapeutic effects of chloroquine. There are currently no reports of its efficacy using the larger and more stringent guinea pig model of infection. In this study we have shown that replication of live EBOV is impaired by chloroquine . However, no protective effects were observed when EBOV-infected guinea pigs were treated with chloroquine. These results advocate that chloroquine should not be considered as a treatment strategy for EBOV.

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© 2015 The Authors
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2015-12-01
2024-04-19
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References

  1. Accapezzato D., Visco V., Francavilla V., Molette C., Donato T., Paroli M., Mondelli M. U., Doria M., Torrisi M. R., Barnaba V. 2005; Chloroquine enhances human CD8+ T cell responses against soluble antigens in vivo. J Exp Med 202:817–828 [View Article][PubMed]
     [Google Scholar]
  2. Adams M. J., Carstens E. B. 2012; Ratification vote on taxonomic proposals to the International Committee on Taxonomy of Viruses (2012). Arch Virol 157:1411–1422 [View Article][PubMed]
     [Google Scholar]
  3. Aderounmu A. F., Salako L. A., Lindström B., Walker O., Ekman L. 1986; Comparison of the pharmacokinetics of chloroquine after single intravenous and intramuscular administration in healthy Africans. Br J Clin Pharmacol 22:559–564 [View Article][PubMed]
     [Google Scholar]
  4. Baize S., Pannetier D., Oestereich L., Rieger T., Koivogui L., Magassouba N., Soropogui B., Sow M. S., Keı¨ta S., other authors. 2014; Emergence of Zaire Ebola virus disease in Guinea. N Engl J Med 371:1418–1425 [View Article][PubMed]
     [Google Scholar]
  5. Center for Drug Evaluation and Research 2005 Guidance for Industry. Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers Washington, DC: US Department of Health and Human Services;
     [Google Scholar]
  6. Chandran K., Sullivan N. J., Felbor U., Whelan S. P., Cunningham J. M. 2005; Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science 308:1643–1645 [View Article][PubMed]
     [Google Scholar]
  7. De Lamballerie X., Boisson V., Reynier J. C., Enault S., Charrel R. N., Flahault A., Roques P., Le Grand R. 2008; On chikungunya acute infection and chloroquine treatment. Vector Borne Zoonotic Dis 8:837–840 [View Article][PubMed]
     [Google Scholar]
  8. Delogu I., de Lamballerie X. 2011; Chikungunya disease and chloroquine treatment. J Med Virol 83:1058–1059 [View Article][PubMed]
     [Google Scholar]
  9. Di Trani L., Savarino A., Campitelli L., Norelli S., Puzelli S., D'Ostilio D., Vignolo E., Donatelli I., Cassone A. 2007; Different pH requirements are associated with divergent inhibitory effects of chloroquine on human and avian influenza A viruses. Virol J 4:39 [View Article][PubMed]
     [Google Scholar]
  10. Diebold S. S., Kaisho T., Hemmi H., Akira S., Reis e Sousa C. 2004; Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303:1529–1531 [View Article][PubMed]
     [Google Scholar]
  11. Dowall S., Taylor I., Yeates P., Smith L., Rule A., Easterbrook L., Bruce C., Cook N., Corbin-Lickfett K., other authors. 2013; Catheterized guinea pigs infected with Ebola Zaire virus allows safer sequential sampling to determine the pharmacokinetic profile of a phosphatidylserine-targeting monoclonal antibody. Antiviral Res 97:108–111 [View Article][PubMed]
     [Google Scholar]
  12. Dowall S. D., Matthews D. A., Garcia-Dorival I., Taylor I., Kenny J., Hertz-Fowler C., Hall N., Corbin-Lickfett K., Empig C., other authors. 2014; Elucidating variations in the nucleotide sequence of Ebola virus associated with increasing pathogenicity. Genome Biol 15:540 [View Article][PubMed]
     [Google Scholar]
  13. Ducharme J., Farinotti R. 1996; Clinical pharmacokinetics and metabolism of chloroquine. Focus on recent advancements. Clin Pharmacokinet 31:257–274 [View Article][PubMed]
     [Google Scholar]
  14. Ekins S., Freundlich J. S., Coffee M. 2014; A common feature pharmacophore for FDA-approved drugs inhibiting the Ebola virus. F1000 Res 3:277[PubMed]
     [Google Scholar]
  15. Falzarano D., Safronetz D., Prescott J., Marzi A., Feldmann F., Feldmann H. 2015; Lack of protection against Ebola virus from chloroquine in mice and hamsters. Emerg Infect Dis 21:1065–1067 [View Article][PubMed]
     [Google Scholar]
  16. Farias K. J., Machado P. R., de Almeida Junior R. F., de Aquino A. A., da Fonseca B. A. 2014; Chloroquine interferes with dengue-2 virus replication in U937 cells. Microbiol Immunol 58:318–326 [View Article][PubMed]
     [Google Scholar]
  17. Farias K. J., Machado P. R., Muniz J. A., Imbeloni A. A., da Fonseca B. A. 2015; Antiviral activity of chloroquine against dengue virus type 2 replication in aotus monkeys. Viral Immunol 28:161–169 [View Article][PubMed]
     [Google Scholar]
  18. Ferraris O., Moroso M., Pernet O., Emonet S., Ferrier Rembert A., Paranhos-Baccalà G., Peyrefitte C. N. 2015; Evaluation of Crimean-Congo hemorrhagic fever virus in vitro inhibition by chloroquine and chlorpromazine, two FDA approved molecules. Antiviral Res 118:75–81 [View Article][PubMed]
     [Google Scholar]
  19. Freiberg A. N., Worthy M. N., Lee B., Holbrook M. R. 2010; Combined chloroquine and ribavirin treatment does not prevent death in a hamster model of Nipah and Hendra virus infection. J Gen Virol 91:765–772 [View Article][PubMed]
     [Google Scholar]
  20. García-Dorival I., Wu W., Dowall S., Armstrong S., Touzelet O., Wastling J., Barr J. N., Matthews D., Carroll M., other authors. 2014; Elucidation of the Ebola virus VP24 cellular interactome and disruption of virus biology through targeted inhibition of host-cell protein function. J Proteome Res 13:5120–5135 [View Article][PubMed]
     [Google Scholar]
  21. Glushakova S. E., Lukashevich I. S. 1989; Early events in arenavirus replication are sensitive to lysosomotropic compounds. Arch Virol 104:157–161 [View Article][PubMed]
     [Google Scholar]
  22. Gustafsson L. L., Walker O., Alván G., Beermann B., Estevez F., Gleisner L., Lindström B., Sjöqvist F. 1983; Disposition of chloroquine in man after single intravenous and oral doses. Br J Clin Pharmacol 15:471–479 [View Article][PubMed]
     [Google Scholar]
  23. Jang C. H., Choi J. H., Byun M. S., Jue D. M. 2006; Chloroquine inhibits production of TNF-α, IL-1β and IL-6 from lipopolysaccharide-stimulated human monocytes/macrophages by different modes. Rheumatology (Oxford) 45:703–710 [View Article][PubMed]
     [Google Scholar]
  24. Keyaerts E., Vijgen L., Maes P., Neyts J., Van Ranst M. 2004; In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem Biophys Res Commun 323:264–268 [View Article][PubMed]
     [Google Scholar]
  25. Keyaerts E., Li S., Vijgen L., Rysman E., Verbeeck J., Van Ranst M., Maes P. 2009; Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice. Antimicrob Agents Chemother 53:3416–3421 [View Article][PubMed]
     [Google Scholar]
  26. Khan M., Santhosh S. R., Tiwari M., Lakshmana Rao P. V., Parida M. 2010; Assessment of in vitro prophylactic and therapeutic efficacy of chloroquine against chikungunya virus in Vero cells. J Med Virol 82:817–824 [View Article][PubMed]
     [Google Scholar]
  27. Kouznetsova J., Sun W., Martínez-Romero C., Tawa G., Shinn P., Chen C. Z., Schimmer A., Sanderson P., McKew J. C., other authors. 2014; Identification of 53 compounds that block Ebola virus-like particle entry via a repurposing screen of approved drugs. Emerg Microbes Infect 3:e84 [View Article][PubMed]
     [Google Scholar]
  28. Kronenberger P., Vrijsen R., Boeyé A. 1991; Chloroquine induces empty capsid formation during poliovirus eclipse. J Virol 65:7008–7011[PubMed]
     [Google Scholar]
  29. Kuhn J. H., Becker S., Ebihara H., Geisbert T. W., Johnson K. M., Kawaoka Y., Lipkin W. I., Negredo A. I., Netesov S. V., other authors. 2010; Proposal for a revised taxonomy of the family Filoviridae: classification, names of taxa and viruses, and virus abbreviations. Arch Virol 155:2083–2103 [View Article][PubMed]
     [Google Scholar]
  30. Kuhn J. H., Lofts L. L., Kugelman J. R., Smither S. J., Lever M. S., van der Groen G., Johnson K. M., Radoshitzky S. R., Bavari S., other authors. 2014; Reidentification of Ebola virus E718 and ME as Ebola virus/H.sapiens-tc/COD/1976/Yambuku-Ecran. Genome Announc 2:e01178–14 [View Article][PubMed]
     [Google Scholar]
  31. Long J., Wright E., Molesti E., Temperton N., Barclay W. 2015; Antiviral therapies against Ebola and other emerging viral diseases using existing medicines that block virus entry. F1000 Res 4:30[PubMed]
     [Google Scholar]
  32. Madrid P. B., Chopra S., Manger I. D., Gilfillan L., Keepers T. R., Shurtleff A. C., Green C. E., Iyer L. V., Dilks H. H., other authors. 2013; A systematic screen of FDA-approved drugs for inhibitors of biological threat agents. PLoS One 8:e60579 [View Article][PubMed]
     [Google Scholar]
  33. Mahanty S., Bray M. 2004; Pathogenesis of filoviral haemorrhagic fevers. Lancet Infect Dis 4:487–498 [View Article][PubMed]
     [Google Scholar]
  34. Martinson J. A., Montoya C. J., Usuga X., Ronquillo R., Landay A. L., Desai S. N. 2010; Chloroquine modulates HIV-1-induced plasmacytoid dendritic cell alpha interferon: implication for T-cell activation. Antimicrob Agents Chemother 54:871–881 [View Article][PubMed]
     [Google Scholar]
  35. Nujić K., Banjanac M., Munić V., Polančec D., Eraković Haber V. 2012; Impairment of lysosomal functions by azithromycin and chloroquine contributes to anti-inflammatory phenotype. Cell Immunol 279:78–86 [View Article][PubMed]
     [Google Scholar]
  36. Ooi E. E., Chew J. S., Loh J. P., Chua R. C. 2006; In vitro inhibition of human influenza A virus replication by chloroquine. Virol J 3:39 [View Article][PubMed]
     [Google Scholar]
  37. Pallister J., Middleton D., Crameri G., Yamada M., Klein R., Hancock T. J., Foord A., Shiell B., Michalski W., other authors. 2009; Chloroquine administration does not prevent Nipah virus infection and disease in ferrets. J Virol 83:11979–11982 [View Article][PubMed]
     [Google Scholar]
  38. Paton N. I., Lee L., Xu Y., Ooi E. E., Cheung Y. B., Archuleta S., Wong G., Smith A. W. 2011; Chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial. Lancet Infect Dis 11:677–683 [View Article][PubMed]
     [Google Scholar]
  39. Porotto M., Orefice G., Yokoyama C. C., Mungall B. A., Realubit R., Sganga M. L., Aljofan M., Whitt M., Glickman F., Moscona A. 2009; Simulating henipavirus multicycle replication in a screening assay leads to identification of a promising candidate for therapy. J Virol 83:5148–5155 [View Article][PubMed]
     [Google Scholar]
  40. Randolph V. B., Winkler G., Stollar V. 1990; Acidotropic amines inhibit proteolytic processing of flavivirus prM protein. Virology 174:450–458 [View Article][PubMed]
     [Google Scholar]
  41. Rolain J. M., Colson P., Raoult D. 2007; Recycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the 21st century. Int J Antimicrob Agents 30:297–308 [View Article][PubMed]
     [Google Scholar]
  42. Savarino A. 2011; Use of chloroquine in viral diseases. Lancet Infect Dis 11:653–654 [View Article][PubMed]
     [Google Scholar]
  43. Savarino A., Gennero L., Sperber K., Boelaert J. R. 2001; The anti-HIV-1 activity of chloroquine. J Clin Virol 20:131–135 [View Article][PubMed]
     [Google Scholar]
  44. Savarino A., Boelaert J. R., Cassone A., Majori G., Cauda R. 2003; Effects of chloroquine on viral infections: an old drug against today's diseases?. Lancet Infect Dis 3:722–727 [View Article][PubMed]
     [Google Scholar]
  45. Towner J. S., Rollin P. E., Bausch D. G., Sanchez A., Crary S. M., Vincent M., Lee W. F., Spiropoulou C. F., Ksiazek T. G., other authors. 2004; Rapid diagnosis of Ebola hemorrhagic fever by reverse transcription-PCR in an outbreak setting and assessment of patient viral load as a predictor of outcome. J Virol 78:4330–4341 [View Article][PubMed]
     [Google Scholar]
  46. Tricou V., Minh N. N., Van T. P., Lee S. J., Farrar J., Wills B., Tran H. T., Simmons C. P. 2010; A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults. PLoS Negl Trop Dis 4:e785 [View Article][PubMed]
     [Google Scholar]
  47. Trombley A. R., Wachter L., Garrison J., Buckley-Beason V. A., Jahrling J., Hensley L. E., Schoepp R. J., Norwood D. A., Goba A., other authors. 2010; Comprehensive panel of real-time TaqManTM polymerase chain reaction assays for detection and absolute quantification of filoviruses, arenaviruses, and New World hantaviruses. Am J Trop Med Hyg 82:954–960 [View Article][PubMed]
     [Google Scholar]
  48. Tsiang H., Superti F. 1984; Ammonium chloride and chloroquine inhibit rabies virus infection in neuroblastoma cells. Arch Virol 81:377–382 [View Article][PubMed]
     [Google Scholar]
  49. Vigerust D. J., McCullers J. A. 2007; Chloroquine is effective against influenza A virus in vitro but not in vivo . Influenza Other Resp Viruses 1:189–192 [View Article][PubMed]
     [Google Scholar]
  50. Vincent M. J., Bergeron E., Benjannet S., Erickson B. R., Rollin P. E., Ksiazek T. G., Seidah N. G., Nichol S. T. 2005; Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J 2:69 [View Article][PubMed]
     [Google Scholar]
  51. Wauquier N., Becquart P., Padilla C., Baize S., Leroy E. M. 2010; Human fatal Zaire Ebola virus infection is associated with an aberrant innate immunity and with massive lymphocyte apoptosis. PLoS Negl Trop Dis 4:e837 [View Article][PubMed]
     [Google Scholar]
  52. Wool-Lewis R. J., Bates P. 1998; Characterization of Ebola virus entry by using pseudotyped viruses: identification of receptor-deficient cell lines. J Virol 72:3155–3160[PubMed]
     [Google Scholar]
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Chloroquine inhibited Ebola virus replication in vitro but failed to protect against infection and disease in the in vivo guinea pig model
J. Gen. Virol. 96, 3484 (2015); https://doi.org/10.1099/jgv.0.000309
/content/journal/jgv/10.1099/jgv.0.000309
/content/journal/jgv/10.1099/jgv.0.000309
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