Potent Dengue Virus Neutralization by a Therapeutic Antibody with Low Monovalent Affinity Requires Bivalent Engagement
Dengue virus (DENV) is a globally important mosquito-transmitted human pathogen for which there is no approved vaccine or antiviral therapy. In recent years, the number and severity of DENV human infections have increased due to the expanded geographic range of the virus. Neutralizing antibodies are a key component of a protective natural and vaccine-induced immune response against human DENV infections. One recently described monoclonal antibody (E106) protects mice against infection of DENV-1 when administered before or several days after virus infection. Because of these results, we investigated the mechanism of action of E106 using a combination of structural and functional approaches. E106 engaged an epitope on domain III of the viral envelope protein that is a composite of two previously described epitopes. Unexpectedly, and in contrast to the intact IgG, Fab fragments of E106 were ineffective at neutralizing virus; this was explained by their weak micromolar affinity for virus particles. Our results suggest that neutralization by E106, our most potently inhibitory and protective anti-DENV MAb, requires bivalent binding of adjacent DIII subunits on a single virion. Immunization strategies with intact virions that skew the selection of neutralizing antibodies to those with bivalently binding properties could augment the potency of antiviral humoral responses against DENV and other flaviviruses.
Vyšlo v časopise:
Potent Dengue Virus Neutralization by a Therapeutic Antibody with Low Monovalent Affinity Requires Bivalent Engagement. PLoS Pathog 10(4): e32767. doi:10.1371/journal.ppat.1004072
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1004072
Souhrn
Dengue virus (DENV) is a globally important mosquito-transmitted human pathogen for which there is no approved vaccine or antiviral therapy. In recent years, the number and severity of DENV human infections have increased due to the expanded geographic range of the virus. Neutralizing antibodies are a key component of a protective natural and vaccine-induced immune response against human DENV infections. One recently described monoclonal antibody (E106) protects mice against infection of DENV-1 when administered before or several days after virus infection. Because of these results, we investigated the mechanism of action of E106 using a combination of structural and functional approaches. E106 engaged an epitope on domain III of the viral envelope protein that is a composite of two previously described epitopes. Unexpectedly, and in contrast to the intact IgG, Fab fragments of E106 were ineffective at neutralizing virus; this was explained by their weak micromolar affinity for virus particles. Our results suggest that neutralization by E106, our most potently inhibitory and protective anti-DENV MAb, requires bivalent binding of adjacent DIII subunits on a single virion. Immunization strategies with intact virions that skew the selection of neutralizing antibodies to those with bivalently binding properties could augment the potency of antiviral humoral responses against DENV and other flaviviruses.
Zdroje
1. BhattS, GethingPW, BradyOJ, MessinaJP, FarlowAW, et al. (2013) The global distribution and burden of dengue. Nature 496: 504–507 doi:10.1038/nature12060
2. Rico-HesseR (1990) Molecular evolution and distribution of dengue viruses type 1 and 2 in nature. Virology 174: 479–493 doi:10.1016/0042-6822(90)90102-W
3. HolmesEC, TwiddySS (2003) The origin, emergence and evolutionary genetics of dengue virus. Infect Genet Evol 3: 19–28 doi:S1567134803000042 [pii]
4. SabinAB (1952) Research on dengue during World War II. Am J Trop Med Hyg 1: 30–50.
5. ReichNG, ShresthaS, KingAA, RohaniP, LesslerJ, et al. (2013) Interactions between serotypes of dengue highlight epidemiological impact of cross-immunity. J R Soc Interface 10 doi:10.1098/rsif.2013.0414
6. HalsteadSB (1989) Antibody, macrophages, dengue virus infection, shock, and hemorrhage: a pathogenetic cascade. Rev Infect Dis 11 Suppl 4: S830–9 doi:10.1111/j.1742-4658.2005.04870.x
7. PiersonTC, FremontDH, KuhnRJ, DiamondMS (2008) Structural insights into the mechanisms of antibody-mediated neutralization of flavivirus infection: implications for vaccine development. Cell Host Microbe 4: 229–238 doi:S1931-3128(08)00260-6 [pii] 10.1016/j.chom.2008.08.004
8. ReyFA, HeinzFX, MandlC, KunzC, HarrisonSC (1995) The envelope glycoprotein from tick-borne encephalitis virus at 2 A resolution. Nature 375: 291–298 doi:10.1038/375291a0
9. ModisY, OgataS, ClementsD, HarrisonSC (2003) A ligand-binding pocket in the dengue virus envelope glycoprotein. Proc Natl Acad Sci U S A 100: 6986–6991 doi:10.1073/pnas.0832193100 0832193100 [pii]
10. CockburnJJ, Navarro SanchezME, FretesN, UrvoasA, StaropoliI, et al. (2012) Mechanism of dengue virus broad cross-neutralization by a monoclonal antibody. Structure 20: 303–314 doi:S0969-2126(12)00005-6 [pii] 10.1016/j.str.2012.01.001
11. CockburnJJ, Navarro SanchezME, GoncalvezAP, ZaitsevaE, SturaEA, et al. (2011) Structural insights into the neutralization mechanism of a higher primate antibody against dengue virus. EMBO J 31: 767–779 doi:emboj2011439 [pii] 10.1038/emboj.2011.439
12. GromowskiGD, BarrettAD (2007) Characterization of an antigenic site that contains a dominant, type-specific neutralization determinant on the envelope protein domain III (ED3) of dengue 2 virus. Virology 366: 349–360 doi:S0042-6822(07)00379-0 [pii] 10.1016/j.virol.2007.05.042
13. ShresthaB, BrienJD, Sukupolvi-PettyS, AustinSK, EdelingMA, et al. (2010) The development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1. PLoS Pathog 6: e1000823 doi:10.1371/journal.ppat.1000823
14. WahalaWM, DonaldsonEF, De AlwisR, Accavitti-LoperMA, BaricRS, et al. (2010) Natural strain variation and antibody neutralization of dengue serotype 3 viruses. PLoS Pathog 6: e1000821 doi:10.1371/journal.ppat.1000821
15. Sukupolvi-PettyS, AustinSK, EngleM, BrienJD, DowdKA, et al. (2010) Structure and function analysis of therapeutic monoclonal antibodies against dengue virus type 2. J Virol 84: 9227–9239 doi:JVI.01087-10 [pii] 10.1128/JVI.01087-10
16. RoehrigJT, BolinRA, KellyRG (1998) Monoclonal antibody mapping of the envelope glycoprotein of the dengue 2 virus, Jamaica. Virology 246: 317–328 doi:S0042-6822(98)99200-5 [pii] 10.1006/viro.1998.9200
17. MidgleyCM, FlanaganA, TranHB, DejnirattisaiW, ChawansuntatiK, et al. (2012) Structural analysis of a dengue cross-reactive antibody complexed with envelope domain III reveals the molecular basis of cross-reactivity. J Immunol 188: 4971–4979 doi:10.4049/jimmunol.1200227
18. ThompsonBS, MoeskerB, SmitJM, WilschutJ, DiamondMS, et al. (2009) A therapeutic antibody against west nile virus neutralizes infection by blocking fusion within endosomes. PLoS Pathog 5: e1000453 doi:10.1371/journal.ppat.1000453
19. WuKP, WuCW, TsaoYP, KuoTW, LouYC, et al. (2003) Structural basis of a flavivirus recognized by its neutralizing antibody: solution structure of the domain III of the Japanese encephalitis virus envelope protein. J Biol Chem 278: 46007–46013 doi:10.1074/jbc.M307776200 M307776200 [pii]
20. NybakkenGE, OliphantT, JohnsonS, BurkeS, DiamondMS, et al. (2005) Structural basis of West Nile virus neutralization by a therapeutic antibody. Nature 437: 764–769 doi:nature03956 [pii] 10.1038/nature03956
21. LokSM, KostyuchenkoV, NybakkenGE, HoldawayHA, BattistiAJ, et al. (2008) Binding of a neutralizing antibody to dengue virus alters the arrangement of surface glycoproteins. Nat Struct Mol Biol 15: 312–317 doi:nsmb.1382 [pii] 10.1038/nsmb.1382
22. ShresthaB, AustinSK, DowdKA, PrasadAN, YounS, et al. (2012) Complex phenotypes in mosquitoes and mice associated with neutralization escape of a Dengue virus type 1 monoclonal antibody. Virology 427: 127–134 doi:S0042-6822(12)00105-5 [pii] 10.1016/j.virol.2012.02.010
23. LawrenceMC, ColmanPM (1993) Shape complementarity at protein/protein interfaces. J Mol Biol 234: 946–950 doi:S0022-2836(83)71648-7 [pii] 10.1006/jmbi.1993.1648
24. KrissinelE, HenrickK (2007) Inference of macromolecular assemblies from crystalline state. J Mol Biol 372: 774–797 doi:S0022-2836(07)00642-0 [pii] 10.1016/j.jmb.2007.05.022
25. DaviesDR, PadlanEA, SheriffS (1990) Antibody-antigen complexes. Annu Rev Biochem 59: 439–473 doi:10.1146/annurev.bi.59.070190.002255
26. SundbergEJ, MariuzzaRA (2002) Molecular recognition in antibody-antigen complexes. Adv Protein Chem 61: 119–160.
27. NelsonS, JostCA, XuQ, EssJ, MartinJE, et al. (2008) Maturation of West Nile Virus Modulates Sensitivity to Antibody-Mediated Neutralization. PLoS Pathog 4: e1000060 doi:10.1371/journal.ppat.1000060
28. DowdKA, JostCA, DurbinAP, WhiteheadSS, PiersonTC (2011) A dynamic landscape for antibody binding modulates antibody-mediated neutralization of West Nile virus. PLoS Pathog 7: e1002111 doi:10.1371/journal.ppat.1002111
29. BeigelJH, NordstromJL, PillemerSR, RoncalC, GoldwaterDR, et al. (2010) Safety and Pharmacokinetics of Single Intravenous Dose of MGAWN1, a Novel Monoclonal Antibody to West Nile Virus. Antimicrob Agents Chemother 54: 2431–2436 doi:10.1128/AAC.01178-09
30. OliphantT, EngleM, NybakkenGE, DoaneC, JohnsonS, et al. (2005) Development of a humanized monoclonal antibody with therapeutic potential against West Nile virus. Nat Med 11: 522–530 doi:nm1240 [pii] 10.1038/nm1240
31. RodrigoWWSI, BlockOKT, LaneC, Sukupolvi-PettyS, GoncalvezAP, et al. (2009) Dengue virus neutralization is modulated by IgG antibody subclass and Fcgamma receptor subtype. Virology 394: 175–182 doi:10.1016/j.virol.2009.09.024
32. Ansarah-SobrinhoC, NelsonS, JostCA, WhiteheadSS, PiersonTC (2008) Temperature-dependent production of pseudoinfectious dengue reporter virus particles by complementation. Virology 381: 67–74 doi:S0042-6822(08)00525-4 [pii] 10.1016/j.virol.2008.08.021
33. AustinSK, DowdKA, ShresthaB, NelsonCA, EdelingMA, et al. (2012) Structural Basis of Differential Neutralization of DENV-1 Genotypes by an Antibody that Recognizes a Cryptic Epitope. PLoS Pathog 8: e1002930 doi:10.1371/journal.ppat.1002930
34. StiasnyK, KiermayrS, HolzmannH, HeinzFX (2006) Cryptic properties of a cluster of dominant flavivirus cross-reactive antigenic sites. J Virol 80: 9557–9568 doi:10.1128/JVI.00080-06
35. SmithTJ, OlsonNH, ChengRH, ChaseES, BakerTS (1993) Structure of a human rhinovirus-bivalently bound antibody complex: implications for viral neutralization and antibody flexibility. Proc Natl Acad Sci USA 90: 7015–7018 doi:10.1073/pnas.90.15.7015
36. HewatEA, BlaasD (1996) Structure of a neutralizing antibody bound bivalently to human rhinovirus 2. EMBO J 15: 1515–1523.
37. ThouveninE, LaurentS, MadelaineM-F, RasschaertD, VautherotJ-F, et al. (1997) Bivalent binding of a neutralising antibody to a calicivirus involves the torsional flexibility of the antibody hinge. Journal of Molecular Biology 270: 238–246 doi:10.1006/jmbi.1997.1095
38. ZhangW, ChipmanPR, CorverJ, JohnsonPR, ZhangY, et al. (2003) Visualization of membrane protein domains by cryo-electron microscopy of dengue virus. Nat Struct Mol Biol 10: 907–912 doi:10.1038/nsb990
39. KaufmannB, NybakkenGE, ChipmanPR, ZhangW, DiamondMS, et al. (2006) West Nile virus in complex with the Fab fragment of a neutralizing monoclonal antibody. Proc Natl Acad Sci U S A 103: 12400–12404 doi:0603488103 [pii] 10.1073/pnas.0603488103
40. SosnickTR, BenjaminDC, NovotnyJ, SeegerPA, TrewhellaJ (1992) Distances between the antigen-binding sites of three murine antibody subclasses measured using neutron and X-ray scattering. Biochemistry 31: 1779–1786 doi:10.1021/bi00121a028
41. FibriansahG, NgT-S, KostyuchenkoVA, LeeJ, LeeS, et al. (2013) Structural changes in dengue virus when exposed to a temperature of 37°C. J Virol 87: 7585–7592 doi:10.1128/JVI.00757-13
42. ZhangX, ShengJ, PlevkaP, KuhnRJ, DiamondMS, et al. (2013) Dengue structure differs at the temperatures of its human and mosquito hosts. Proc Natl Acad Sci USA 110: 6795–6799 doi:10.1073/pnas.1304300110
43. CherrierMV, KaufmannB, NybakkenGE, LokSM, WarrenJT, et al. (2009) Structural basis for the preferential recognition of immature flaviviruses by a fusion-loop antibody. EMBO J 28: 3269–3276 doi:emboj2009245 [pii] 10.1038/emboj.2009.245
44. KaufmannB, VogtMR, GoudsmitJ, HoldawayHA, AksyukAA, et al. (2010) Neutralization of West Nile virus by cross-linking of its surface proteins with Fab fragments of the human monoclonal antibody CR4354. Proc Natl Acad Sci U S A 107: 18950–18955 doi:1011036107 [pii] 10.1073/pnas.1011036107
45. De AlwisR, SmithSA, OlivarezNP, MesserWB, HuynhJP, et al. (2012) Identification of human neutralizing antibodies that bind to complex epitopes on dengue virions. Proc Natl Acad Sci USA 109: 7439–7444 doi:10.1073/pnas.1200566109
46. TeohEP, KukkaroP, TeoEW, LimAPC, TanTT, et al. (2012) The structural basis for serotype-specific neutralization of dengue virus by a human antibody. Sci Transl Med 4: 139ra83 doi:10.1126/scitranslmed.3003888
47. KuhnRJ, ZhangW, RossmannMG, PletnevSV, CorverJ, et al. (2002) Structure of dengue virus: implications for flavivirus organization, maturation, and fusion. Cell 108: 717–725 doi:S0092867402006608 [pii]
48. ModisY, OgataS, ClementsD, HarrisonSC (2004) Structure of the dengue virus envelope protein after membrane fusion. Nature 427: 313–319 doi:10.1038/nature02165 nature02165 [pii]
49. BrienJD, AustinSK, Sukupolvi-PettyS, O'BrienKM, JohnsonS, et al. (2010) Genotype-specific neutralization and protection by antibodies against dengue virus type 3. J Virol 84: 10630–10643 doi:JVI.01190-10 [pii] 10.1128/JVI.01190-10
50. ThomasAA, VrijsenR, BoeyeA (1986) Relationship between poliovirus neutralization and aggregation. J Virol 59: 479–485.
51. KaufmannB, ChipmanPR, HoldawayHA, JohnsonS, FremontDH, et al. (2009) Capturing a flavivirus pre-fusion intermediate. PLoS Pathog 5: e1000672 doi:10.1371/journal.ppat.1000672
52. SmithTJ, OlsonNH, ChengRH, LiuH, ChaseES, et al. (1993) Structure of human rhinovirus complexed with Fab fragments from a neutralizing antibody. J Virol 67: 1148–1158.
53. MouquetH, ScheidJF, ZollerMJ, KrogsgaardM, OttRG, et al. (2010) Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation. Nature 467: 591–595 doi:nature09385 [pii] 10.1038/nature09385
54. ZhuP, LiuJ, BessJ, ChertovaE, LifsonJD, et al. (2006) Distribution and three-dimensional structure of AIDS virus envelope spikes. Nature 441: 847–852 doi:nature04817 [pii] 10.1038/nature04817
55. SchofieldDJ, StephensonJR, DimmockNJ (1997) Variations in the neutralizing and haemagglutination-inhibiting activities of five influenza A virus-specific IgGs and their antibody fragments. J Gen Virol 78(Pt 10): 2431–2439.
56. KlassePJ, SattentauQJ (2002) Occupancy and mechanism in antibody-mediated neutralization of animal viruses. J Gen Virol 83: 2091–2108.
57. Otwinowski Z, Minor W (1997) Processing of X-ray diffraction data collected in oscillation mode. In: C.WCarter J& RMS, editors. Methods in Enzymology. New York: Academic Press. pp. 307–326.
58. McCoyAJ, Grosse-KunstleveRW, AdamsPD, WinnMD, StoroniLC, et al. (2007) Phaser crystallographic software. J Appl Crystallogr 40: 658–674 doi:10.1107/S0021889807021206
59. EmsleyP, CowtanK (2004) Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 60: 2126–2132 doi:S0907444904019158 [pii] 10.1107/S0907444904019158
60. MurshudovGN, VaginAA, DodsonEJ (1997) Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr D Biol Crystallogr 53: 240–255 doi:10.1107/S0907444996012255 S0907444996012255 [pii]
61. AdamsPD, AfoninePV, BunkócziG, ChenVB, DavisIW, et al. (2010) PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallographica Section D Biological Crystallography 66: 213–221 doi:10.1107/S0907444909052925
62. PottertonL, McNicholasS, KrissinelE, GruberJ, CowtanK, et al. (2004) Developments in the CCP4 molecular-graphics project. Acta Crystallogr D Biol Crystallogr 60: 2288–2294 doi:10.1107/S0907444904023716
63. DeLano WL (2008) The PyMOL Molecular Graphics System, version 1. Schrödinger, LLC (Oregon).
64. VogtMR, MoeskerB, GoudsmitJ, JongeneelenM, AustinSK, et al. (2009) Human monoclonal antibodies against West Nile virus induced by natural infection neutralize at a postattachment step. J Virol 83: 6494–6507 doi:JVI.00286-09 [pii] 10.1128/JVI.00286-09
65. MattiaK, PufferBA, WilliamsKL, GonzalezR, MurrayM, et al. (2011) Dengue reporter virus particles for measuring neutralizing antibodies against each of the four dengue serotypes. PLoS ONE 6: e27252 doi:10.1371/journal.pone.0027252
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Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
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