Ebola Virus Entry into Host Cells: Identifying Therapeutic Strategies

Current Clinical Microbiology Reports

Volumn 2, Issue 3, 2015, Pages 115-124

  Rhein, Bethany A ^a   Maury, Wendy J ^a  

^a UNIVERSITY OF IOWA   (United States)

Author keywords

C type lectins; Ebola virus; Filoviruses; NPC1; Phosphatidylserine receptors; Proteolytic processing; Therapeutics; Virus entry; Virus receptors

Indexed keywords

EID: 84975303912     PISSN: None     EISSN: 21965471     Source Type: Journal    
DOI: 10.1007/s40588-015-0021-3     Document Type: Review

References (106)

1. Kuhn JH, Becker S, Ebihara H, Geisbert TW, Johnson KM, Kawaoka Y, et al. Proposal for a revised taxonomy of the family Filoviridae: classification, names of taxa and viruses, and virus abbreviations. Arch Virol. 2010;155(12):2083–103.
2. Feldmann H, Geisbert TW. Ebola haemorrhagic fever. Lancet. 2011;377(9768):849–62.
3. Centers for Disease Control and Prevention 2014 Ebola outbreak in West Africa[May 11, 2015]. Available from http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/index.html.
4. Leroy EM, Gonzalez JP, Baize S. Ebola and Marburg haemorrhagic fever viruses: major scientific advances, but a relatively minor public health threat for Africa. Clin Microbiol Infect. 2011;17(7):964–76.
5. Martines RB, Ng DL, Greer PW, Rollin PE, Zaki SR. Tissue and cellular tropism, pathology and pathogenesis of Ebola and Marburg viruses. J Pathol. 2015;235(2):153–74.
6. Geisbert TW, Hensley LE, Gibb TR, Steele KE, Jaax NK, Jahrling PB. Apoptosis induced in vitro and in vivo during infection by Ebola and Marburg viruses. Lab Investig; J Techn Method Pathol. 2000;80(2):171–86.
7. Jemielity S, Wang JJ, Chan YK, Ahmed AA, Li W, Monahan S, et al. TIM-family proteins promote infection of multiple enveloped viruses through virion-associated phosphatidylserine. PLoS Pathog. 2013;9(3):e1003232. Identified that TIM and TAM proteins bind to PtdSer in virion envelopes to promote infection of a wide array of enveloped viruses including filoviruses, flaviviruses, New World arenaviruses and alphaviruses.
8. Moller-Tank S, Kondratowicz AS, Davey RA, Rennert PD, Maury W. Role of the phosphatidylserine receptor TIM-1 in enveloped-virus entry. J Virol. 2013;87(15):8327–41. Defined the molecular interactions between TIM-1 and PtdSer on the surface of Ebola virus virions. They also demonstrated that TIM-1 can enhance infection of alphavirus and baculovirus families.
9. Noda T, Kolesnikova L, Becker S, Kawaoka Y. The importance of the NP: VP35 ratio in Ebola virus nucleocapsid formation. J Infect Dis. 2011;204 Suppl 3:S878–83.
10. Becker S, Rinne C, Hofsass U, Klenk HD, Muhlberger E. Interactions of Marburg virus nucleocapsid proteins. Virology. 1998;249(2):406–17.
11. Groseth A, Charton JE, Sauerborn M, Feldmann F, Jones SM, Hoenen T, et al. The Ebola virus ribonucleoprotein complex: a novel VP30-L interaction identified. Virus Res. 2009;140(1-2):8–14.
12. Hoenen T, Jung S, Herwig A, Groseth A, Becker S. Both matrix proteins of Ebola virus contribute to the regulation of viral genome replication and transcription. Virology. 2010;403(1):56–66.
13. Harrison SC. Viral membrane fusion. Virology. 2015. doi:: 10.1016/j.virol.2015.03.043
14. Sanchez A, Yang ZY, Xu L, Nabel GJ, Crews T, Peters CJ. Biochemical analysis of the secreted and virion glycoproteins of Ebola virus. J Virol. 1998;72(8):6442–7.
15. Audet J, Kobinger GP. Immune evasion in ebolavirus infections. Viral Immunol. 2015;28(1):10–8.
16. Sanchez A, Trappier SG, Mahy BW, Peters CJ, Nichol ST. The virion glycoproteins of Ebola viruses are encoded in two reading frames and are expressed through transcriptional editing. Proc Natl Acad Sci U S A. 1996;93(8):3602–7.
17. Feldmann H, Volchkov VE, Volchkova VA, Klenk HD. The glycoproteins of Marburg and Ebola virus and their potential roles in pathogenesis. Arch Virol Suppl. 1999;15:159–69.
18. Volchkov VE, Feldmann H, Volchkova VA, Klenk HD. Processing of the Ebola virus glycoprotein by the proprotein convertase furin. Proc Natl Acad Sci U S A. 1998;95(10):5762–7.
19. Lee JE, Fusco ML, Hessell AJ, Oswald WB, Burton DR, Saphire EO. Structure of the Ebola virus glycoprotein bound to an antibody from a human survivor. Nature. 2008;454(7201):177–82.
20. Dias JM, Kuehne AI, Abelson DM, Bale S, Wong AC, Halfmann P, et al. A shared structural solution for neutralizing ebolaviruses. Nat Struct Mol Biol. 2011;18(12):1424–7.
21. Hashiguchi T, Fusco ML, Bornholdt ZA, Lee JE, Flyak AI, Matsuoka R, et al. Structural basis for Marburg virus neutralization by a cross-reactive human antibody. Cell. 2015;160(5):904–12. Determined the crystal structure of Marburg virus GP utilizing antibodies from a human survivor. They identified that the mucin-containing domain of MARV is arranged differently that that domain in EBOV. This explains why antibodies targeting the base of MARV GP1 have yet to be identified.
22. Feldmann H, Nichol ST, Klenk HD, Peters CJ, Sanchez A. Characterization of filoviruses based on differences in structure and antigenicity of the virion glycoprotein. Virology. 1994;199(2):469–73.
23. Lennemann NJ, Rhein BA, Ndungo E, Chandran K, Qiu X, Maury W. Comprehensive functional analysis of N-linked glycans on Ebola virus GP1. mBio. 2014;5(1):e00862–13. Demonstrated the importance of N-linked and O-linked glycans of the EBOV GP MLD, core and glycan cap in C-type lectin mediated EBOV entry as well as the other role these glycans play in the EBOV biology.
24. Wilson JA, Hevey M, Bakken R, Guest S, Bray M, Schmaljohn AL. Epitopes involved in antibody-mediated protection from Ebola virus. Science (New York, NY). 2000;287(5458):1664–6.
25. Dowling W, Thompson E, Badger C, Mellquist JL, Garrison AR, Smith JM, et al. Influences of glycosylation on antigenicity, immunogenicity, and protective efficacy of ebola virus GP DNA vaccines. J Virol. 2007;81(4):1821–37.
26. Martinez O, Tantral L, Mulherkar N, Chandran K, Basler CF. Impact of Ebola mucin-like domain on antiglycoprotein antibody responses induced by Ebola virus-like particles. J Infect Dis. 2011;204 Suppl 3:S825–32.
27. Ito H, Watanabe S, Sanchez A, Whitt MA, Kawaoka Y. Mutational analysis of the putative fusion domain of Ebola virus glycoprotein. J Virol. 1999;73(10):8907–12.
28. Jeffers SA, Sanders DA, Sanchez A. Covalent modifications of the ebola virus glycoprotein. J Virol. 2002;76(24):12463–72.
29. White JM, Delos SE, Brecher M, Schornberg K. Structures and mechanisms of viral membrane fusion proteins: multiple variations on a common theme. Crit Rev Biochem Mol Biol. 2008;43(3):189–219.
30. Gregory SM, Harada E, Liang B, Delos SE, White JM, Tamm LK. Structure and function of the complete internal fusion loop from Ebolavirus glycoprotein 2. Proc Natl Acad Sci U S A. 2011;108(27):11211–6.
31. Mason CP, Tarr AW. Human lectins and their roles in viral infections. Molecules (Basel, Switzerland). 2015;20(2):2229–71.
32. Moller-Tank S, Maury W. Phosphatidylserine receptors: enhancers of enveloped virus entry and infection. Virology. 2014;468-470:565–80.
33. Alvarez CP, Lasala F, Carrillo J, Muniz O, Corbi AL, Delgado R. C-type lectins DC-SIGN and L-SIGN mediate cellular entry by Ebola virus in cis and in trans. J Virol. 2002;76(13):6841–4.
34. Takada A, Fujioka K, Tsuiji M, Morikawa A, Higashi N, Ebihara H, et al. Human macrophage C-type lectin specific for galactose and N-acetylgalactosamine promotes filovirus entry. J Virol. 2004;78(6):2943–7.
35. Powlesland AS, Fisch T, Taylor ME, Smith DF, Tissot B, Dell A, et al. A novel mechanism for LSECtin binding to Ebola virus surface glycoprotein through truncated glycans. J Biol Chem. 2008;283(1):593–602.
36. Becker S, Spiess M, Klenk HD. The asialoglycoprotein receptor is a potential liver-specific receptor for Marburg virus. J Gen Virol. 1995;76(Pt 2):393–9.
37. Dahlmann F, Biedenkopf N, Babler A, Jahnen-Dechent W, Karsten CB, Gnirss K, et al. Analysis of Ebola virus entry into macrophages. J Infect Dis. 2015. doi: 10.1093/infdis/jiv140
38. Marzi A, Akhavan A, Simmons G, Gramberg T, Hofmann H, Bates P, et al. The signal peptide of the ebolavirus glycoprotein influences interaction with the cellular lectins DC-SIGN and DC-SIGNR. J Virol. 2006;80(13):6305–17.
39. Marzi A, Moller P, Hanna SL, Harrer T, Eisemann J, Steinkasserer A, et al. Analysis of the interaction of Ebola virus glycoprotein with DC-SIGN (dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin) and its homologue DC-SIGNR. J Infect Dis. 2007;196 Suppl 2:S237–46.
40. Simmons G, Reeves JD, Grogan CC, Vandenberghe LH, Baribaud F, Whitbeck JC, et al. DC-SIGN and DC-SIGNR bind ebola glycoproteins and enhance infection of macrophages and endothelial cells. Virology. 2003;305(1):115–23.
41. Lin G, Simmons G, Pohlmann S, Baribaud F, Ni H, Leslie GJ, et al. Differential N-linked glycosylation of human immunodeficiency virus and Ebola virus envelope glycoproteins modulates interactions with DC-SIGN and DC-SIGNR. J Virol. 2003;77(2):1337–46.
42. Gramberg T, Caminschi I, Wegele A, Hofmann H, Pohlmann S. Evidence that multiple defects in murine DC-SIGN inhibit a functional interaction with pathogens. Virology. 2006;345(2):482–91.
43. Pipirou Z, Powlesland AS, Steffen I, Pohlmann S, Taylor ME, Drickamer K. Mouse LSECtin as a model for a human Ebola virus receptor. Glycobiology. 2011;21(6):806–12.
44. Shimojima M, Takada A, Ebihara H, Neumann G, Fujioka K, Irimura T, et al. Tyro3 family-mediated cell entry of Ebola and Marburg viruses. J Virol. 2006;80(20):10109–16.
45. Hunt CL, Kolokoltsov AA, Davey RA, Maury W. The Tyro3 receptor kinase Axl enhances macropinocytosis of Zaire ebolavirus. J Virol. 2011;85(1):334–47.
46. Morizono K, Chen IS. Role of phosphatidylserine receptors in enveloped virus infection. J Virol. 2014;88(8):4275–90.
47. Saeed MF, Kolokoltsov AA, Albrecht T, Davey RA. Cellular entry of ebola virus involves uptake by a macropinocytosis-like mechanism and subsequent trafficking through early and late endosomes. PLoS Pathog. 2010;6(9):e1001110.
48. Empig CJ, Goldsmith MA. Association of the caveola vesicular system with cellular entry by filoviruses. J Virol. 2002;76(10):5266–70.
49. Nanbo A, Imai M, Watanabe S, Noda T, Takahashi K, Neumann G, et al. Ebolavirus is internalized into host cells via macropinocytosis in a viral glycoprotein-dependent manner. PLoS Pathog. 2010;6(9):e1001121.
50. Bhattacharyya S, Warfield KL, Ruthel G, Bavari S, Aman MJ, Hope TJ. Ebola virus uses clathrin-mediated endocytosis as an entry pathway. Virology. 2010;401(1):18–28.
51. Aleksandrowicz P, Marzi A, Biedenkopf N, Beimforde N, Becker S, Hoenen T, et al. Ebola virus enters host cells by macropinocytosis and clathrin-mediated endocytosis. J Infect Dis. 2011;204 Suppl 3:S957–67.
52. Mulherkar N, Raaben M, de la Torre JC, Whelan SP, Chandran K. The Ebola virus glycoprotein mediates entry via a non-classical dynamin-dependent macropinocytic pathway. Virology. 2011;419(2):72–83.
53. Bhattacharyya S, Hope TJ, Young JA. Differential requirements for clathrin endocytic pathway components in cellular entry by Ebola and Marburg glycoprotein pseudovirions. Virology. 2011;419(1):1–9.
54. Bhattacharyya S, Mulherkar N, Chandran K. Endocytic pathways involved in filovirus entry: advances, implications and future directions. Viruses. 2012;4(12):3647–64.
55. Saeed MF, Kolokoltsov AA, Freiberg AN, Holbrook MR, Davey RA. Phosphoinositide-3 kinase-Akt pathway controls cellular entry of Ebola virus. PLoS Pathog. 2008;4(8):e1000141.
56. Kondratowicz AS, Lennemann NJ, Sinn PL, Davey RA, Hunt CL, Moller-Tank S, et al. T-cell immunoglobulin and mucin domain 1 (TIM-1) is a receptor for Zaire Ebolavirus and Lake Victoria Marburgvirus. Proc Natl Acad Sci U S A. 2011;108(20):8426–31.
57. Kondratowicz AS, Hunt CL, Davey RA, Cherry S, Maury WJ. AMP-activated protein kinase is required for the macropinocytic internalization of ebolavirus. J Virol. 2013;87(2):746–55.
58. Miller EH, Chandran K. Filovirus entry into cells - new insights. Curr Opin Virol. 2012;2(2):206–14.
59. Moller-Tank S, Maury W. Ebola virus entry: a curious and complex series of events. PLoS Pathog. 2015;11(4):e1004731.
60. Mingo RM, Simmons JA, Shoemaker CJ, Nelson EA, Schornberg KL, D’Souza RS, et al. Ebola virus and severe acute respiratory syndrome coronavirus display late cell entry kinetics: evidence that transport to NPC1+ endolysosomes is a rate-defining step. J Virol. 2015;89(5):2931–43. Provided evidence of the slow kinetics of EBOV entry. Also demonstrated that EBOV traffics late into the endocytic pathway to NPC1+ late endo/lysosomal vesicles, where there are higher levels of cathepsin activity, suggesting the need for additional proteolysis following NPC1 interaction for fusion to occur.
61. Quinn K, Brindley MA, Weller ML, Kaludov N, Kondratowicz A, Hunt CL, et al. Rho GTPases modulate entry of Ebola virus and vesicular stomatitis virus pseudotyped vectors. J Virol. 2009;83(19):10176–86.
62. Kolokoltsov AA, Saeed MF, Freiberg AN, Holbrook MR, Davey RA. Identification of novel cellular targets for therapeutic intervention against Ebola virus infection by siRNA screening. Drug Dev Res. 2009;70(4):255–65.
63. Carette JE, Raaben M, Wong AC, Herbert AS, Obernosterer G, Mulherkar N, et al. Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. Nature. 2011;477(7364):340–3.
64. Wong AC, Sandesara RG, Mulherkar N, Whelan SP, Chandran K. A forward genetic strategy reveals destabilizing mutations in the Ebolavirus glycoprotein that alter its protease dependence during cell entry. J Virol. 2010;84(1):163–75.
65. Brecher M, Schornberg KL, Delos SE, Fusco ML, Saphire EO, White JM. Cathepsin cleavage potentiates the Ebola virus glycoprotein to undergo a subsequent fusion-relevant conformational change. J Virol. 2012;86(1):364–72.
66. Chandran K, Sullivan NJ, Felbor U, Whelan SP, Cunningham JM. Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science (New York, NY). 2005;308(5728):1643–5.
67. Schornberg K, Matsuyama S, Kabsch K, Delos S, Bouton A, White J. Role of endosomal cathepsins in entry mediated by the Ebola virus glycoprotein. J Virol. 2006;80(8):4174–8.
68. Dube D, Brecher MB, Delos SE, Rose SC, Park EW, Schornberg KL, et al. The primed ebolavirus glycoprotein (19-kilodalton GP1,2): sequence and residues critical for host cell binding. J Virol. 2009;83(7):2883–91.
69. Hood CL, Abraham J, Boyington JC, Leung K, Kwong PD, Nabel GJ. Biochemical and structural characterization of cathepsin L-processed Ebola virus glycoprotein: implications for viral entry and immunogenicity. J Virol. 2010;84(6):2972–82.
70. Misasi J, Chandran K, Yang JY, Considine B, Filone CM, Cote M, et al. Filoviruses require endosomal cysteine proteases for entry but exhibit distinct protease preferences. J Virol. 2012;86(6):3284–92. Characterized the cathepsin B and L dependency of different EBOV species. Identified that different filovirus species have altered utilization of cathepsin L and B alone or in combination.
71. Marzi A, Reinheckel T, Feldmann H. Cathepsin B & L are not required for ebola virus replication. PLoS Negl Trop Dis. 2012;6(12):e1923. Demonstrated no differences in survival or morbidity of cathepsin B and L single-knockout mice compared to wild-type mice following lethal EBOV challenge. These results suggest that neither of these proteases are specifically and absolutely required for in vivo EBOV infection.
72. Martinez O, Johnson J, Manicassamy B, Rong L, Olinger GG, Hensley LE, et al. Zaire Ebola virus entry into human dendritic cells is insensitive to cathepsin L inhibition. Cell Microbiol. 2010;12(2):148–57.
73. Cote M, Misasi J, Ren T, Bruchez A, Lee K, Filone CM, et al. Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection. Nature. 2011;477(7364):344–8.
74. Miller EH, Obernosterer G, Raaben M, Herbert AS, Deffieu MS, Krishnan A, et al. Ebola virus entry requires the host-programmed recognition of an intracellular receptor. EMBO J. 2012;31(8):1947–60. Identified that cleaved filovirus GP interacts directly with the luminal C-loop of NPC1 and this interaction is important for entry steps in the late endosome/lysosome.
75. Hunt CL, Lennemann NJ, Maury W. Filovirus entry: a novelty in the viral fusion world. Viruses. 2012;4(2):258–75.
76. White JM, Schornberg KL. A new player in the puzzle of filovirus entry. Nat Rev Microbiol. 2012;10(5):317–22.
77. van der Kant R, Zondervan I, Janssen L, Neefjes J. Cholesterol-binding molecules MLN64 and ORP1L mark distinct late endosomes with transporters ABCA3 and NPC1. J Lipid Res. 2013;54(8):2153–65.
78. Carstea ED, Morris JA, Coleman KG, Loftus SK, Zhang D, Cummings C. Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science (New York, NY). 1997;277(5323):228–31.
79. Higgins ME, Davies JP, Chen FW, Ioannou YA. Niemann-Pick C1 is a late endosome-resident protein that transiently associates with lysosomes and the trans-Golgi network. Mol Genet Metab. 1999;68(1):1–13.
80. Krishnan A, Miller EH, Herbert AS, Ng M, Ndungo E, Whelan SP, et al. Niemann-Pick C1 (NPC1)/NPC1-like1 chimeras define sequences critical for NPC1’s function as a flovirus entry receptor. Viruses. 2012;4(11):2471–84.
81. Kuroda M, Fujikura D, Nanbo A, Marzi A, Noyori O, Kajihara M, et al. The interaction between TIM-1 and NPC1 Is important for the cellular entry of Ebola virus. J Virol. 2015. doi: 10.1128/JVI.03156-14
82. Gehring G, Rohrmann K, Atenchong N, Mittler E, Becker S, Dahlmann F, et al. The clinically approved drugs amiodarone, dronedarone and verapamil inhibit filovirus cell entry. J Antimicrob Chemother. 2014;69(8):2123–31.
83. Sakurai Y, Kolokoltsov AA, Chen CC, Tidwell MW, Bauta WE, Klugbauer N. Ebola virus. Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment. Science (New York, NY). 2015;347(6225):995–8. The first demonstration of the importance of L-type calcium channels in Ebola virus entry. They also demonstrate the ability of calcium channel inhibitors to protect mice against lethal Ebola virus challenge.
84. Genazzani AA, Mezna M, Dickey DM, Michelangeli F, Walseth TF, Galione A. Pharmacological properties of the Ca2+-release mechanism sensitive to NAADP in the sea urchin egg. Br J Pharmacol. 1997;121(7):1489–95.
85. Bale S, Dias JM, Fusco ML, Hashiguchi T, Wong AC, Liu T, et al. Structural basis for differential neutralization of ebolaviruses. Viruses. 2012;4(4):447–70.
86. Gregory SM, Larsson P, Nelson EA, Kasson PM, White JM, Tamm LK. Ebolavirus entry requires a compact hydrophobic fist at the tip of the fusion loop. J Virol. 2014;88(12):6636–49. Demonstrated that the conformation of the hydrophobic tip of the GP2 fusion loop changes under low pH conditions and identifies two residues in the fusion loop (I544 and L529) that are critical for forming a consolidated hydrophobic surface at the tip of the loop.
87. Weissenhorn W, Carfi A, Lee KH, Skehel JJ, Wiley DC. Crystal structure of the Ebola virus membrane fusion subunit, GP2, from the envelope glycoprotein ectodomain. Mol Cell. 1998;2(5):605–16.
88. Picazo E, Giordanetto F. Small molecule inhibitors of ebola virus infection. Drug Discov Today. 2015;20(2):277–86.
89. Barrientos LG, Rollin PE. Release of cellular proteases into the acidic extracellular milieu exacerbates Ebola virus-induced cell damage. Virology. 2007;358(1):1–9.
90. Gnirss K, Kuhl A, Karsten C, Glowacka I, Bertram S, Kaup F, et al. Cathepsins B and L activate Ebola but not Marburg virus glycoproteins for efficient entry into cell lines and macrophages independent of TMPRSS2 expression. Virology. 2012;424(1):3–10.
91. Shah PP, Wang T, Kaletsky RL, Myers MC, Purvis JE, Jing H, et al. A small-molecule oxocarbazate inhibitor of human cathepsin L blocks severe acute respiratory syndrome and ebola pseudotype virus infection into human embryonic kidney 293T cells. Mol Pharmacol. 2010;78(2):319–24.
92. Zhou Y, Vedantham P, Lu K, Agudelo J, Carrion Jr R, Nunneley JW, et al. Protease inhibitors targeting coronavirus and filovirus entry. Antivir Res. 2015;116:76–84.
93. Cenedella RJ. Cholesterol synthesis inhibitor U18666A and the role of sterol metabolism and trafficking in numerous pathophysiological processes. Lipids. 2009;44(6):477–87.
94. Rodriguez-Lafrasse C, Rousson R, Bonnet J, Pentchev PG, Louisot P, Vanier MT. Abnormal cholesterol metabolism in imipramine-treated fibroblast cultures. Similarities with Niemann-Pick type C disease. Biochim Biophys Acta. 1990;1043(2):123–8.
95. Shoemaker CJ, Schornberg KL, Delos SE, Scully C, Pajouhesh H, Olinger GG, et al. Multiple cationic amphiphiles induce a Niemann-Pick C phenotype and inhibit Ebola virus entry and infection. PLoS One. 2013;8(2):e56265.
96. Miller ME, Adhikary S, Kolokoltsov AA, Davey RA. Ebolavirus requires acid sphingomyelinase activity and plasma membrane sphingomyelin for infection. J Virol. 2012;86(14):7473–83.
97. Lee K, Ren T, Cote M, Gholamreza B, Misasi J, Bruchez A, et al. Inhibition of Ebola virus infection: identification of Niemann-Pick C1 as the target by optimization of a chemical probe. ACS Med Chem Lett. 2013;4(2):239–43.
98. Johansen LM, Brannan JM, Delos SE, Shoemaker CJ, Stossel A, Lear C. FDA-approved selective estrogen receptor modulators inhibit Ebola virus infection. Sci Transl Med. 2013;5(190):190ra79.
99. Pettitt J, Zeitlin L, Kim do H, Working C, Johnson JC, Bohorov O. Therapeutic intervention of Ebola virus infection in rhesus macaques with the MB-003 monoclonal antibody cocktail. Sci Transl Med. 2013;5(199):199ra13.
100. Qiu X, Audet J, Wong G, Pillet S, Bello A, Cabral T, et al. Successful treatment of ebola virus-infected cynomolgus macaques with monoclonal antibodies. Sci Transl Med. 2012;4(138):138ra81.
101. Qiu X, Wong G, Audet J, Bello A, Fernando L, Alimonti JB, et al. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature. 2014;514(7520):47–53. Demonstrated the ability of the ZMapp antibody cocktail to protect 100 % of rhesus macaques when treatment is performed up to 5 days following lethal EBOV challenge.
102. Maruyama T, Rodriguez LL, Jahrling PB, Sanchez A, Khan AS, Nichol ST, et al. Ebola virus can be effectively neutralized by antibody produced in natural human infection. J Virol. 1999;73(7):6024–30.
103. Parren PW, Geisbert TW, Maruyama T, Jahrling PB, Burton DR. Pre- and postexposure prophylaxis of Ebola virus infection in an animal model by passive transfer of a neutralizing human antibody. J Virol. 2002;76(12):6408–12.
104. Oswald WB, Geisbert TW, Davis KJ, Geisbert JB, Sullivan NJ, Jahrling PB, et al. Neutralizing antibody fails to impact the course of Ebola virus infection in monkeys. PLoS Pathog. 2007;3(1):e9.
105. Audet J, Wong G, Wang H, Lu G, Gao GF, Kobinger G, et al. Molecular characterization of the monoclonal antibodies composing ZMAb: a protective cocktail against Ebola virus. Scientif Rep. 2014;4:6881. Described the epitope binding properties of ZMAb antibodies 1H3, 2G4 and 4G7.
106. Murin CD, Fusco ML, Bornholdt ZA, Qiu X, Olinger GG, Zeitlin L, et al. Structures of protective antibodies reveal sites of vulnerability on Ebola virus. Proc Natl Acad Sci U S A. 2014;111(48):17182–7. Described the binding of mAbs from the ZMapp, MB-003 and ZMAb cocktails, identifying the targeted sites for antibody binding of the EBOV glycoprotein.