Structural Basis for the Recognition of Human Cytomegalovirus Glycoprotein B by a Neutralizing Human Antibody

English version České info

Human cytomegalovirus (HCMV) belongs to the family of β-herpes viruses. HCMV infections are not only life threatening to people with a compromised immune system but also the most common viral cause of congenital defects in newborns. Hence, the development of HCMV vaccines was ranked top priority by the US Institute of Medicine in 1999. Virtually all infected individuals develop antibodies against the envelope protein gB, which plays a crucial role in the infection process. Here, we describe the crystal structure of a fragment of the virus neutralizing antibody SM5-1 in complex with an antigenic determinant of gB, namely Dom-II. The structure shows that antigen antibody interactions are concentrated within two CDRs of SM5-1. Computational methods and an analysis of additional antibody sequences from the same lineage reveal that additional key contributions to high affinity binding are provided by residues that stiffen the extra-long CDR H3 loop without directly contacting the antigen. We suggest that the optimization of such indirect contributions represents a common and yet undervalued principle of the antibody maturation process. Furthermore our data suggest that the neutralizing effect of SM5-1 either originates from blocking membrane fusion or from preventing interaction of gB with other envelope proteins.

Vyšlo v časopise: Structural Basis for the Recognition of Human Cytomegalovirus Glycoprotein B by a Neutralizing Human Antibody. PLoS Pathog 10(10): e32767. doi:10.1371/journal.ppat.1004377
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004377

Souhrn

Zdroje

1. Britt W (2006) Human cytomegalovirus infections and mechanisms of disease. In: Reddehase MJ, editor. Cytomegaloviruses: molecular biology and immunology. Norfolk (UK): Caister Academic Press. pp. 1–28.

2. KennesonA, CannonMJ (2007) Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol 17: 253–276.

3. ArvinAM, FastP, MyersM, PlotkinS, RabinovichR, et al. (2004) Vaccine development to prevent cytomegalovirus disease: report from the National Vaccine Advisory Committee. Clin Infect Dis 39: 233–239.

4. ConnollySA, JacksonJO, JardetzkyTS, LongneckerR (2011) Fusing structure and function: a structural view of the herpesvirus entry machinery. Nat Rev Microbiol 9: 369–381.

5. FeireAL, KossH, ComptonT (2004) Cellular integrins function as entry receptors for human cytomegalovirus via a highly conserved disintegrin-like domain. Proc Natl Acad Sci U S A 101: 15470–15475.

6. WangX, HuongSM, ChiuML, Raab-TraubN, HuangES (2003) Epidermal growth factor receptor is a cellular receptor for human cytomegalovirus. Nature 424: 456–461.

7. SoroceanuL, AkhavanA, CobbsCS (2008) Platelet-derived growth factor-alpha receptor activation is required for human cytomegalovirus infection. Nature 455: 391–395.

8. VanarsdallAL, WisnerTW, LeiH, KazlauskasA, JohnsonDC (2012) PDGF receptor-alpha does not promote HCMV entry into epithelial and endothelial cells but increased quantities stimulate entry by an abnormal pathway. PLoS Pathog 8: e1002905.

9. IsaacsonMK, FeireAL, ComptonT (2007) Epidermal growth factor receptor is not required for human cytomegalovirus entry or signaling. J Virol 81: 6241–6247.

10. EisenbergRJ, AtanasiuD, CairnsTM, GallagherJR, KrummenacherC, et al. (2012) Herpes virus fusion and entry: a story with many characters. Viruses 4: 800–832.

11. RyckmanBJ, RainishBL, ChaseMC, BortonJA, NelsonJA, et al. (2008) Characterization of the human cytomegalovirus gH/gL/UL128-131 complex that mediates entry into epithelial and endothelial cells. J Virol 82: 60–70.

12. HahnG, RevelloMG, PatroneM, PercivalleE, CampaniniG, et al. (2004) Human cytomegalovirus UL131-128 genes are indispensable for virus growth in endothelial cells and virus transfer to leukocytes. J Virol 78: 10023–10033.

13. ComptonT, NepomucenoRR, NowlinDM (1992) Human cytomegalovirus penetrates host cells by pH-independent fusion at the cell surface. Virology 191: 387–395.

14. SinzgerC (2008) Entry route of HCMV into endothelial cells. J Clin Virol 41: 174–179.

15. RyckmanBJ, JarvisMA, DrummondDD, NelsonJA, JohnsonDC (2006) Human cytomegalovirus entry into epithelial and endothelial cells depends on genes UL128 to UL150 and occurs by endocytosis and low-pH fusion. J Virol 80: 710–722.

16. HaspotF, LavaultA, SinzgerC, Laib SampaioK, StierhofYD, et al. (2012) Human cytomegalovirus entry into dendritic cells occurs via a macropinocytosis-like pathway in a pH-independent and cholesterol-dependent manner. PLoS One 7: e34795.

17. BackovicM, LongneckerR, JardetzkyTS (2009) Structure of a trimeric variant of the Epstein-Barr virus glycoprotein B. Proc Natl Acad Sci U S A 106: 2880–2885.

18. HeldweinEE, LouH, BenderFC, CohenGH, EisenbergRJ, et al. (2006) Crystal structure of glycoprotein B from herpes simplex virus 1. Science 313: 217–220.

19. RocheS, ReyFA, GaudinY, BressanelliS (2007) Structure of the prefusion form of the vesicular stomatitis virus glycoprotein G. Science 315: 843–848.

20. RocheS, BressanelliS, ReyFA, GaudinY (2006) Crystal structure of the low-pH form of the vesicular stomatitis virus glycoprotein G. Science 313: 187–191.

21. KadlecJ, LoureiroS, AbresciaNG, StuartDI, JonesIM (2008) The postfusion structure of baculovirus gp64 supports a unified view of viral fusion machines. Nat Struct Mol Biol 15: 1024–1030.

22. MarshallGS, RabalaisGP, StoutGG, WaldeyerSL (1992) Antibodies to recombinant-derived glycoprotein B after natural human cytomegalovirus infection correlate with neutralizing activity. J Infect Dis 165: 381–384.

23. BrittWJ, VuglerL, ButfiloskiEJ, StephensEB (1990) Cell surface expression of human cytomegalovirus (HCMV) gp55-116 (gB): use of HCMV-recombinant vaccinia virus-infected cells in analysis of the human neutralizing antibody response. J Virol 64: 1079–1085.

24. PassRF, ZhangC, EvansA, SimpsonT, AndrewsW, et al. (2009) Vaccine prevention of maternal cytomegalovirus infection. N Engl J Med 360: 1191–1199.

25. GriffithsPD, StantonA, McCarrellE, SmithC, OsmanM, et al. (2011) Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial. Lancet 377: 1256–1263.

26. PotzschS, SpindlerN, WiegersAK, FischT, RuckerP, et al. (2011) B cell repertoire analysis identifies new antigenic domains on glycoprotein B of human cytomegalovirus which are target of neutralizing antibodies. PLoS Pathog 7: e1002172.

27. BackovicM, JardetzkyTS (2009) Class III viral membrane fusion proteins. Curr Opin Struct Biol 19: 189–196.

28. AtanasiuD, WhitbeckJC, de LeonMP, LouH, HannahBP, et al. (2010) Bimolecular complementation defines functional regions of Herpes simplex virus gB that are involved with gH/gL as a necessary step leading to cell fusion. J Virol 84: 3825–3834.

29. WuCH, ApweilerR, BairochA, NataleDA, BarkerWC, et al. (2006) The Universal Protein Resource (UniProt): an expanding universe of protein information. Nucleic Acids Res 34: D187–191.

30. ScheffzekK, WeltiS (2012) Pleckstrin homology (PH) like domains - versatile modules in protein-protein interaction platforms. FEBS Lett 586: 2662–2673.

31. StampferSD, LouH, CohenGH, EisenbergRJ, HeldweinEE (2010) Structural basis of local, pH-dependent conformational changes in glycoprotein B from herpes simplex virus type 1. J Virol 84: 12924–12933.

32. SpindlerN, RuckerP, PotzschS, DiestelU, StichtH, et al. (2013) Characterization of a discontinuous neutralizing epitope on glycoprotein B of human cytomegalovirus. J Virol 87: 8927–8939.

33. MeyerH, MasuhoY, MachM (1990) The gp116 of the gp58/116 complex of human cytomegalovirus represents the amino-terminal part of the precursor molecule and contains a neutralizing epitope. J Gen Virol 71 (Pt 10) 2443–2450.

34. SpaeteRR, SaxenaA, ScottPI, SongGJ, ProbertWS, et al. (1990) Sequence requirements for proteolytic processing of glycoprotein B of human cytomegalovirus strain Towne. J Virol 64: 2922–2931.

35. HolmL, ParkJ (2000) DaliLite workbench for protein structure comparison. Bioinformatics 16: 566–567.

36. StanfieldRL, ZemlaA, WilsonIA, RuppB (2006) Antibody elbow angles are influenced by their light chain class. J Mol Biol 357: 1566–1574.

37. WilsonIA, StanfieldRL (1994) Antibody-antigen interactions: new structures and new conformational changes. Curr Opin Struct Biol 4: 857–867.

38. EkiertDC, KashyapAK, SteelJ, RubrumA, BhabhaG, et al. (2012) Cross-neutralization of influenza A viruses mediated by a single antibody loop. Nature 489: 526–532.

39. WellsJA (1996) Binding in the growth hormone receptor complex. Proc Natl Acad Sci U S A 93: 1–6.

40. ZemlinM, KlingerM, LinkJ, ZemlinC, BauerK, et al. (2003) Expressed murine and human CDR-H3 intervals of equal length exhibit distinct repertoires that differ in their amino acid composition and predicted range of structures. J Mol Biol 334: 733–749.

41. KurodaD, ShiraiH, KoboriM, NakamuraH (2008) Structural classification of CDR-H3 revisited: a lesson in antibody modeling. Proteins 73: 608–620.

42. MouquetH, ScharfL, EulerZ, LiuY, EdenC, et al. (2012) Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies. Proc Natl Acad Sci U S A 109: E3268–3277.

43. JulienJP, SokD, KhayatR, LeeJH, DooresKJ, et al. (2013) Broadly neutralizing antibody PGT121 allosterically modulates CD4 binding via recognition of the HIV-1 gp120 V3 base and multiple surrounding glycans. PLoS Pathog 9: e1003342.

44. CairnsTM, FontanaJ, HuangZY, WhitbeckJC, AtanasiuD, et al. (2013) Mechanism of neutralization of HSV by antibodies directed at the fusion domain of glycoprotein B. J Virol 88: 2677–89 doi: 10.1128/JVI.03200-13

45. SharmaS, WisnerTW, JohnsonDC, HeldweinEE (2013) HCMV gB shares structural and functional properties with gB proteins from other herpesviruses. Virology 435: 239–249.

46. VituE, SharmaS, StampferSD, HeldweinEE (2013) Extensive mutagenesis of the HSV-1 gB ectodomain reveals remarkable stability of its postfusion form. J Mol Biol 425: 2056–2071.

47. PlateAE, ReimerJJ, JardetzkyTS, LongneckerR (2011) Mapping regions of Epstein-Barr virus (EBV) glycoprotein B (gB) important for fusion function with gH/gL. Virology 413: 26–38.

48. CuiX, MezaBP, AdlerSP, McVoyMA (2008) Cytomegalovirus vaccines fail to induce epithelial entry neutralizing antibodies comparable to natural infection. Vaccine 26: 5760–5766.

49. AxelssonF, AdlerSP, LamarreA, OhlinM (2007) Humoral immunity targeting site I of antigenic domain 2 of glycoprotein B upon immunization with different cytomegalovirus candidate vaccines. Vaccine 26: 41–46.

50. KabschW (2010) Integration, scaling, space-group assignment and post-refinement. Acta Crystallogr D Biol Crystallogr 66: 133–144.

51. McCoyAJ, Grosse-KunstleveRW, AdamsPD, WinnMD, StoroniLC, et al. (2007) Phaser crystallographic software. J Appl Crystallogr 40: 658–674.

52. WinnMD, BallardCC, CowtanKD, DodsonEJ, EmsleyP, et al. (2011) Overview of the CCP4 suite and current developments. Acta Crystallogr D Biol Crystallogr 67: 235–242.

53. SchwarzenbacherR, GodzikA, GrzechnikSK, JaroszewskiL (2004) The importance of alignment accuracy for molecular replacement. Acta Crystallogr D Biol Crystallogr 60: 1229–1236.

54. KrivovGG, ShapovalovMV, DunbrackRLJr (2009) Improved prediction of protein side-chain conformations with SCWRL4. Proteins 77: 778–795.

55. MurshudovGN, SkubakP, LebedevAA, PannuNS, SteinerRA, et al. (2011) REFMAC5 for the refinement of macromolecular crystal structures. Acta Crystallogr D Biol Crystallogr 67: 355–367.

56. ZemlaA, ZhouCE, SlezakT, KuczmarskiT, RamaD, et al. (2005) AS2TS system for protein structure modeling and analysis. Nucleic Acids Res 33: W111–115.

57. BlomN, Sicheritz-PontenT, GuptaR, GammeltoftS, BrunakS (2004) Prediction of post-translational glycosylation and phosphorylation of proteins from the amino acid sequence. Proteomics 4: 1633–1649.

58. TillerT, MeffreE, YurasovS, TsuijiM, NussenzweigMC, et al. (2008) Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. J Immunol Methods 329: 112–124.

59. OlssonMHM, SondergaardCR, RostkowskiM, JensenJH (2011) PROPKA3: Consistent Treatment of Internal and Surface Residues in Empirical pK(a) Predictions. Journal of Chemical Theory and Computation. Journal of Chemical Theory and Computation 7: 525–537.

60. GuexN, PeitschMC (1997) SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18: 2714–2723.

61. HornakV, AbelR, OkurA, StrockbineB, RoitbergA, et al. (2006) Comparison of multiple Amber force fields and development of improved protein backbone parameters. Proteins 65: 712–725.

62. Case DA, Darden TA, Cheatham TE, 3rd, Simmerling C, Wang J, et al.. (2010) AMBER11. San Francisco: University of California.

63. MeiselbachH, HornAHC, HarrerT, StichtH (2007) Insights into amprenavir resistance in E35D HIV-1 protease mutation from molecular dynamics and binding free-energy calculations. J Mol Model 13: 297–304.

64. WarthaF, HornAHC, MeiselbachH, StichtH (2005) Molecular dynamics simulations of HIV-1 protease suggest different mechanisms contributing to drug resistance. Journal of Chemical Theory and Computation 1: 315–324.

65. MiyamotoS, KollmanPA (1992) Settle - an Analytical Version of the Shake and Rattle Algorithm for Rigid Water Models. Journal of Computational Chemistry 13: 952–962.

66. HumphreyW, DalkeA, SchultenK (1996) VMD: visual molecular dynamics. J Mol Graph 14: 33–38, 33-38, 27-38.

67. EmsleyP, CowtanK (2004) Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 60: 2126–2132.

68. KleywegtGJ, JonesTA (1994) Detection, delineation, measurement and display of cavities in macromolecular structures. Acta Crystallogr D Biol Crystallogr 50: 178–185.

69. Bohne-LangA, von der LiethCW (2005) GlyProt: in silico glycosylation of proteins. Nucleic Acids Res 33: W214–219.