1887

Abstract

Marburg virus (MARV) and Ebola virus, members of the family , cause lethal haemorrhagic fever in humans and non-human primates. Although the outbreaks are concentrated mainly in Central Africa, these viruses are potential agents of imported infectious diseases and bioterrorism in non-African countries. Recent studies demonstrated that non-human primates passively immunized with virus-specific antibodies were successfully protected against fatal filovirus infection, highlighting the important role of antibodies in protective immunity for this disease. However, the mechanisms underlying potential evasion from antibody mediated immune pressure are not well understood. To analyse possible mutations involved in immune evasion in the MARV envelope glycoprotein (GP) which is the major target of protective antibodies, we selected escape mutants of recombinant vesicular stomatitis virus (rVSV) expressing MARV GP (rVSVΔG/MARVGP) by using two GP-specific mAbs, AGP127-8 and MGP72-17, which have been previously shown to inhibit MARV budding. Interestingly, several rVSVΔG/MARVGP variants escaping from the mAb pressure-acquired amino acid substitutions in the furin-cleavage site rather than in the mAb-specific epitopes, suggesting that these epitopes are recessed, not exposed on the uncleaved GP molecule, and therefore inaccessible to the mAbs. More surprisingly, some variants escaping mAb MGP72-17 lacked a large proportion of the mucin-like region of GP, indicating that these mutants efficiently escaped the selective pressure by deleting the mucin-like region including the mAb-specific epitope. Our data demonstrate that MARV GP possesses the potential to evade antibody mediated immune pressure due to extraordinary structural flexibility and variability.

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2013-04-01
2019-12-13
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References

  1. Amman B. R., Carroll S. A., Reed Z. D., Sealy T. K., Balinandi S., Swanepoel R., Kemp A., Erickson B. R., Comer J. A.. & other authors ( 2012;). Seasonal pulses of Marburg virus circulation in juvenile Rousettus aegyptiacus bats coincide with periods of increased risk of human infection. . PLoS Pathog 8:, e1002877. [CrossRef][PubMed]
    [Google Scholar]
  2. Brindley M. A., Hughes L., Ruiz A., McCray P. B. Jr, Sanchez A., Sanders D. A., Maury W.. ( 2007;). Ebola virus glycoprotein 1: identification of residues important for binding and postbinding events. . J Virol 81:, 7702–7709. [CrossRef][PubMed]
    [Google Scholar]
  3. Dube D., Brecher M. B., Delos S. E., Rose S. C., Park E. W., Schornberg K. L., Kuhn J. H., White J. M.. ( 2009;). The primed ebolavirus glycoprotein (19-kilodalton GP1,2): sequence and residues critical for host cell binding. . J Virol 83:, 2883–2891. [CrossRef][PubMed]
    [Google Scholar]
  4. Dye J. M., Herbert A. S., Kuehne A. I., Barth J. F., Muhammad M. A., Zak S. E., Ortiz R. A., Prugar L. I., Pratt W. D.. ( 2012;). Postexposure antibody prophylaxis protects nonhuman primates from filovirus disease. . Proc Natl Acad Sci U S A 109:, 5034–5039. [CrossRef][PubMed]
    [Google Scholar]
  5. Feldmann H., Will C., Schikore M., Slenczka W., Klenk H. D.. ( 1991;). Glycosylation and oligomerization of the spike protein of Marburg virus. . Virology 182:, 353–356. [CrossRef][PubMed]
    [Google Scholar]
  6. Feldmann H., Nichol S. T., Klenk H. D., Peters C. J., Sanchez A.. ( 1994;). Characterization of filoviruses based on differences in structure and antigenicity of the virion glycoprotein. . Virology 199:, 469–473. [CrossRef][PubMed]
    [Google Scholar]
  7. Fofana I., Fafi-Kremer S., Carolla P., Fauvelle C., Zahid M. N., Turek M., Heydmann L., Cury K., Hayer J.. & other authors ( 2012;). Mutations that alter use of hepatitis C virus cell entry factors mediate escape from neutralizing antibodies. . Gastroenterology 143:, 223–233. [CrossRef][PubMed]
    [Google Scholar]
  8. Francica J. R., Varela-Rohena A., Medvec A., Plesa G., Riley J. L., Bates P.. ( 2010;). Steric shielding of surface epitopes and impaired immune recognition induced by the Ebola virus glycoprotein. . PLoS Pathog 6:, e1001098. [CrossRef][PubMed]
    [Google Scholar]
  9. García-Barreno B., Portela A., Delgado T., López J. A., Melero J. A.. ( 1990;). Frame shift mutations as a novel mechanism for the generation of neutralization resistant mutants of human respiratory syncytial virus. . EMBO J 9:, 4181–4187.[PubMed]
    [Google Scholar]
  10. Hangartner L., Zinkernagel R. M., Hengartner H.. ( 2006;). Antiviral antibody responses: the two extremes of a wide spectrum. . Nat Rev Immunol 6:, 231–243. [CrossRef][PubMed]
    [Google Scholar]
  11. Holland J. J., Domingo E., de la Torre J. C., Steinhauer D. A.. ( 1990;). Mutation frequencies at defined single codon sites in vesicular stomatitis virus and poliovirus can be increased only slightly by chemical mutagenesis. . J Virol 64:, 3960–3962.[PubMed]
    [Google Scholar]
  12. Ito H., Watanabe S., Takada A., Kawaoka Y.. ( 2001;). Ebola virus glycoprotein: proteolytic processing, acylation, cell tropism, and detection of neutralizing antibodies. . J Virol 75:, 1576–1580. [CrossRef][PubMed]
    [Google Scholar]
  13. Kajihara M., Marzi A., Nakayama E., Noda T., Kuroda M., Manzoor R., Matsuno K., Feldmann H., Yoshida R.. & other authors ( 2012;). Inhibition of Marburg virus budding by nonneutralizing antibodies to the envelope glycoprotein. . J Virol 86:, 13467–13474. [CrossRef][PubMed]
    [Google Scholar]
  14. Kuhn J. H., Radoshitzky S. R., Guth A. C., Warfield K. L., Li W., Vincent M. J., Towner J. S., Nichol S. T., Bavari S.. & other authors ( 2006;). Conserved receptor-binding domains of Lake Victoria Marburgvirus and Zaire Ebolavirus bind a common receptor. . J Biol Chem 281:, 15951–15958. [CrossRef][PubMed]
    [Google Scholar]
  15. Lee J. E., Saphire E. O.. ( 2009;). Neutralizing Ebolavirus: structural insights into the envelope glycoprotein and antibodies targeted against it. . Curr Opin Struct Biol 19:, 408–417. [CrossRef][PubMed]
    [Google Scholar]
  16. Lee J. E., Fusco M. L., Hessell A. J., Oswald W. B., Burton D. R., Saphire E. O.. ( 2008;). Structure of the Ebola virus glycoprotein bound to a human survivor antibody. . Nature 454:, 177–182. [CrossRef][PubMed]
    [Google Scholar]
  17. Manicassamy B., Wang J., Jiang H., Rong L.. ( 2005;). Comprehensive analysis of Ebola virus GP1 in viral entry. . J Virol 79:, 4793–4805. [CrossRef][PubMed]
    [Google Scholar]
  18. Marzi A., Yoshida R., Miyamoto H., Ishijima M., Suzuki Y., Higuchi M., Matsuyama Y., Igarashi M., Nakayama E.. & other authors ( 2012;). Protective efficacy of neutralizing monoclonal antibodies in a nonhuman primate model of Ebola hemorrhagic fever. . PLoS ONE 7:, e36192. [CrossRef][PubMed]
    [Google Scholar]
  19. Matsuno K., Kishida N., Usami K., Igarashi M., Yoshida R., Nakayama E., Shimojima M., Feldmann H., Irimura T.. & other authors ( 2010;). Different potential of C-type lectin-mediated entry between Marburg virus strains. . J Virol 84:, 5140–5147. [CrossRef][PubMed]
    [Google Scholar]
  20. Nakayama E., Takada A.. ( 2011;). Ebola and Marburg viruses. . J Disast Res 6:, 381–389.
    [Google Scholar]
  21. Nakayama E., Tomabechi D., Matsuno K., Kishida N., Yoshida R., Feldmann H., Takada A.. ( 2011;). Antibody-dependent enhancement of Marburg virus infection. . J Infect Dis 204: (Suppl. 3), S978–S985. [CrossRef][PubMed]
    [Google Scholar]
  22. Negredo A., Palacios G., Vázquez-Morón S., González F., Dopazo H., Molero F., Juste J., Quetglas J., Savji N.. & other authors ( 2011;). Discovery of an Ebolavirus-like filovirus in europe. . PLoS Pathog 7:, e1002304. [CrossRef][PubMed]
    [Google Scholar]
  23. Neumann G., Feldmann H., Watanabe S., Lukashevich I., Kawaoka Y.. ( 2002;). Reverse genetics demonstrates that proteolytic processing of the Ebola virus glycoprotein is not essential for replication in cell culture. . J Virol 76:, 406–410. [CrossRef][PubMed]
    [Google Scholar]
  24. Neumann G., Geisbert T. W., Ebihara H., Geisbert J. B., Daddario-DiCaprio K. M., Feldmann H., Kawaoka Y.. ( 2007;). Proteolytic processing of the Ebola virus glycoprotein is not critical for Ebola virus replication in nonhuman primates. . J Virol 81:, 2995–2998. [CrossRef][PubMed]
    [Google Scholar]
  25. Olinger G. G. Jr, Pettitt J., Kim D., Working C., Bohorov O., Bratcher B., Hiatt E., Hume S. D., Johnson A. K.. & other authors ( 2012;). Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques. . Proc Natl Acad Sci U S A 109:, 18030–18035. [CrossRef][PubMed]
    [Google Scholar]
  26. Qiu X., Audet J., Wong G., Pillet S., Bello A., Cabral T., Strong J. E., Plummer F., Corbett C. R.. & other authors ( 2012;). Successful treatment of Ebola virus-infected cynomolgus macaques with monoclonal antibodies. . Sci Transl Med 4:, 138ra81. [CrossRef][PubMed]
    [Google Scholar]
  27. Reynard O., Borowiak M., Volchkova V. A., Delpeut S., Mateo M., Volchkov V. E.. ( 2009;). Ebolavirus glycoprotein GP masks both its own epitopes and the presence of cellular surface proteins. . J Virol 83:, 9596–9601. [CrossRef][PubMed]
    [Google Scholar]
  28. Rowe C. L., Baker S. C., Nathan M. J., Fleming J. O.. ( 1997a;). Evolution of mouse hepatitis virus: detection and characterization of spike deletion variants during persistent infection. . J Virol 71:, 2959–2969.[PubMed]
    [Google Scholar]
  29. Rowe C. L., Fleming J. O., Nathan M. J., Sgro J. Y., Palmenberg A. C., Baker S. C.. ( 1997b;). Generation of coronavirus spike deletion variants by high-frequency recombination at regions of predicted RNA secondary structure. . J Virol 71:, 6183–6190.[PubMed]
    [Google Scholar]
  30. Sanchez A., Geisbert T. W., Feldmann H.. ( 2007;). Filoviridae: Marburg and Ebola viruses. . In Fields Virology, , 5th edn., pp. 1409–1448. Edited by Knipe D. M., Howley P. M... Philadelphia, PA:: Lippincott Williams & Wilkins;.
    [Google Scholar]
  31. Schnell M. J., Buonocore L., Kretzschmar E., Johnson E., Rose J. K.. ( 1996;). Foreign glycoproteins expressed from recombinant vesicular stomatitis viruses are incorporated efficiently into virus particles. . Proc Natl Acad Sci U S A 93:, 11359–11365. [CrossRef][PubMed]
    [Google Scholar]
  32. Shedlock D. J., Bailey M. A., Popernack P. M., Cunningham J. M., Burton D. R., Sullivan N. J.. ( 2010;). Antibody-mediated neutralization of Ebola virus can occur by two distinct mechanisms. . Virology 401:, 228–235. [CrossRef][PubMed]
    [Google Scholar]
  33. Simmons G., Wool-Lewis R. J., Baribaud F., Netter R. C., Bates P.. ( 2002;). Ebola virus glycoproteins induce global surface protein down-modulation and loss of cell adherence. . J Virol 76:, 2518–2528. [CrossRef][PubMed]
    [Google Scholar]
  34. Takada A., Robison C., Goto H., Sanchez A., Murti K. G., Whitt M. A., Kawaoka Y.. ( 1997;). A system for functional analysis of Ebola virus glycoprotein. . Proc Natl Acad Sci U S A 94:, 14764–14769. [CrossRef][PubMed]
    [Google Scholar]
  35. Takada A., Feldmann H., Stroeher U., Bray M., Watanabe S., Ito H., McGregor M., Kawaoka Y.. ( 2003;). Identification of protective epitopes on Ebola virus glycoprotein at the single amino acid level by using recombinant vesicular stomatitis viruses. . J Virol 77:, 1069–1074. [CrossRef][PubMed]
    [Google Scholar]
  36. Takada A., Fujioka K., Tsuiji M., Morikawa A., Higashi N., Ebihara H., Kobasa D., Feldmann H., Irimura T., Kawaoka Y.. ( 2004;). Human macrophage C-type lectin specific for galactose and N-acetylgalactosamine promotes filovirus entry. . J Virol 78:, 2943–2947. [CrossRef][PubMed]
    [Google Scholar]
  37. Towner J. S., Amman B. R., Sealy T. K., Carroll S. A., Comer J. A., Kemp A., Swanepoel R., Paddock C. D., Balinandi S.. & other authors ( 2009;). Isolation of genetically diverse Marburg viruses from Egyptian fruit bats. . PLoS Pathog 5:, e1000536. [CrossRef][PubMed]
    [Google Scholar]
  38. Volchkov V. E., Volchkova V. A., Ströher U., Becker S., Dolnik O., Cieplik M., Garten W., Klenk H. D., Feldmann H.. ( 2000;). Proteolytic processing of Marburg virus glycoprotein. . Virology 268:, 1–6. [CrossRef][PubMed]
    [Google Scholar]
  39. Wilson J. A., Hevey M., Bakken R., Guest S., Bray M., Schmaljohn A. L., Hart M. K.. ( 2000;). Epitopes involved in antibody-mediated protection from Ebola virus. . Science 287:, 1664–1666. [CrossRef][PubMed]
    [Google Scholar]
  40. 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]
  41. Wool-Lewis R. J., Bates P.. ( 1999;). Endoproteolytic processing of the Ebola virus envelope glycoprotein: cleavage is not required for function. . J Virol 73:, 1419–1426.[PubMed]
    [Google Scholar]
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