Envelope Deglycosylation Enhances Antigenicity of HIV-1 gp41 Epitopes for Both Broad Neutralizing Antibodies and Their Unmutated Ancestor Antibodies

English version České info

The HIV-1 gp41 envelope (Env) membrane proximal external region (MPER) is an important vaccine target that in rare subjects can elicit neutralizing antibodies. One mechanism proposed for rarity of MPER neutralizing antibody generation is lack of reverted unmutated ancestor (putative naive B cell receptor) antibody reactivity with HIV-1 envelope. We have studied the effect of partial deglycosylation under non-denaturing (native) conditions on gp140 Env antigenicity for MPER neutralizing antibodies and their reverted unmutated ancestor antibodies. We found that native deglycosylation of clade B JRFL gp140 as well as group M consensus gp140 Env CON-S selectively increased the reactivity of Env with the broad neutralizing human mAbs, 2F5 and 4E10. Whereas fully glycosylated gp140 Env either did not bind (JRFL), or weakly bound (CON-S), 2F5 and 4E10 reverted unmutated ancestors, natively deglycosylated JRFL and CON-S gp140 Envs did bind well to these putative mimics of naive B cell receptors. These data predict that partially deglycoslated Env would bind better than fully glycosylated Env to gp41-specific naïve B cells with improved immunogenicity. In this regard, immunization of rhesus macaques demonstrated enhanced immunogenicity of the 2F5 MPER epitope on deglyosylated JRFL gp140 compared to glycosylated JRFL gp140. Thus, the lack of 2F5 and 4E10 reverted unmutated ancestor binding to gp140 Env may not always be due to lack of unmutated ancestor antibody reactivity with gp41 peptide epitopes, but rather, may be due to glycan interference of binding of unmutated ancestor antibodies of broad neutralizing mAb to Env gp41.

Vyšlo v časopise: Envelope Deglycosylation Enhances Antigenicity of HIV-1 gp41 Epitopes for Both Broad Neutralizing Antibodies and Their Unmutated Ancestor Antibodies. PLoS Pathog 7(9): e32767. doi:10.1371/journal.ppat.1002200
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002200

Souhrn

Zdroje

1. MusterTGuineaRTrkolaAPurtscherMKlimaA 1994 Cross-neutralizing activity against divergent human immunodeficiency virus type 1 isolates induced by the gp41 sequence ELDKWAS. J Virol 68 4031 4034

2. ZwickMBLabrijnAFWangMSpenlehauerCSaphireEO 2001 Broadly neutralizing antibodies targeted to the membrane-proximal external region of human immunodeficiency virus type 1 glycoprotein gp41. J Virol 75 10892 10905

3. ZwickMBJensenRChurchSWangMStieglerG 2005 Anti-human immunodeficiency virus type 1 (HIV-1) antibodies 2F5 and 4E10 require surprisingly few crucial residues in the membrane-proximal external region of glycoprotein gp41 to neutralize HIV-1. J Virol 79 1252 1261

4. OfekGTangMSamborAKatingerHMascolaJR 2004 Structure and mechanistic analysis of the anti-human immunodeficiency virus type 1 antibody 2F5 in complex with its gp41 epitope. J Virol 78 10724 10737

5. CardosoRMZwickMBStanfieldRLKunertRBinleyJM 2005 Broadly neutralizing anti-HIV antibody 4E10 recognizes a helical conformation of a highly conserved fusion-associated motif in gp41. Immunity 22 163 173

6. HaynesBFFlemingJSt ClairEWKatingerHStieglerG 2005 Cardiolipin polyspecific autoreactivity in two broadly neutralizing HIV-1 antibodies. Science 308 1906 1908

7. AlamSMMcAdamsMBorenDRakMScearceRM 2007 The role of antibody polyspecificity and lipid reactivity in binding of broadly neutralizing anti-HIV-1 envelope human monoclonal antibodies 2F5 and 4E10 to glycoprotein 41 membrane proximal envelope epitopes. J Immunol 178 4424 4435

8. AlamSMMorelliMDennisonSMLiaoHXZhangR 2009 Role of HIV membrane in neutralization by two broadly neutralizing antibodies. Proc Natl Acad Sci U S A 106 20234 20239

9. DennisonSMStewartSMStempelKCLiaoHXHaynesBF 2009 Stable docking of neutralizing human immunodeficiency virus type 1 gp41 membrane-proximal external region monoclonal antibodies 2F5 and 4E10 is dependent on the membrane immersion depth of their epitope regions. J Virol 83 10211 10223

10. OfekGMcKeeKYangYYangZYSkinnerJ 2010 Relationship between antibody 2F5 neutralization of HIV-1 and hydrophobicity of its heavy chain third complementarity-determining region. J Virol 84 2955 2962

11. SchererEMLeamanDPZwickMBMcMichaelAJBurtonDR 2010 Aromatic residues at the edge of the antibody combining site facilitate viral glycoprotein recognition through membrane interactions. Proc Natl Acad Sci U S A 107 1529 1534

12. HaynesBFAlamSM 2008 HIV-1 hides an Achilles' heel in virion lipids. Immunity 28 10 12

13. VerkoczyLDiazMHollTMOuyangYBBouton-VervilleH 2010 Autoreactivity in an HIV-1 broadly reactive neutralizing antibody variable region heavy chain induces immunologic tolerance. Proc Natl Acad Sci U S A 107 181 186

14. VerkoczyLBouton-VervilleHHutchinsonJScearceRMLiaoHX 2010 Role of immunoglobulin light chain usage and MPER specificity in counterselecting B cells expressing the broadly neutralizing antibody 2F5. AIDS Res Hum Retroviruses 26 Abstract No. P04.55LB A-155

15. FreyGPengHRits-VollochSMorelliMChengY 2008 A fusion-intermediate state of HIV-1 gp41 targeted by broadly neutralizing antibodies. Proc Natl Acad Sci U S A 105 3739 3744

16. XiaoXChenWFengYZhuZPrabakaranP 2009 Germline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: implications for evasion of immune responses and design of vaccine immunogens. Biochem Biophys Res Commun 390 404 409

17. DooresKJBurtonDR 2010 Variable loop glycan dependency of the broad and potent HIV-1-neutralizing antibodies PG9 and PG16. J Virol 84 10510 10521

18. ReitterJNMeansREDesrosiersRC 1998 A role for carbohydrates in immune evasion in AIDS. Nat Med 4 679 684

19. RichmanDDWrinTLittleSJPetropoulosCJ 2003 Rapid evolution of the neutralizing antibody response to HIV type 1 infection. Proc Natl Acad Sci U S A 100 4144 4149

20. SaphireEOParrenPWPantophletRZwickMBMorrisGM 2001 Crystal structure of a neutralizing human IGG against HIV-1: a template for vaccine design. Science 293 1155 1159

21. WalkerLMPhogatSKChan-HuiPYWagnerDPhungP 2009 Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science 326 285 289

22. WeiXDeckerJMWangSHuiHKappesJC 2003 Antibody neutralization and escape by HIV-1. Nature 422 307 312

23. YusteEBixbyJLifsonJSatoSJohnsonW 2008 Glycosylation of gp41 of simian immunodeficiency virus shields epitopes that can be targets for neutralizing antibodies. J Virol 82 12472 12486

24. ColeKSSteckbeckJDRowlesJLDesrosiersRCMontelaroRC 2004 Removal of N-linked glycosylation sites in the V1 region of simian immunodeficiency virus gp120 results in redirection of B-cell responses to V3. J Virol 78 1525 1539

25. McCaffreyRASaundersCHenselMStamatatosL 2004 N-linked glycosylation of the V3 loop and the immunologically silent face of gp120 protects human immunodeficiency virus type 1 SF162 from neutralization by anti-gp120 and anti-gp41 antibodies. J Virol 78 3279 3295

26. ZhangCWanYShiJZhouMMengZ 2010 Deglycosylation of HIV-1 AE Gp140 enhances the capacity to elicit neutralizing antibodies against the heterologous HIV-1 clade. AIDS Res Hum Retroviruses 26 569 575

27. GnanakaranSDanielsMGBhattacharyaTLapedesASSethiA 2010 Genetic signatures in the envelope glycoproteins of HIV-1 that associate with broadly neutralizing antibodies. PLoS Comput Biol 6 e1000955

28. KirchherrJLHamiltonJWLuXGnanakaranSMuldoonM 2010 Identification of amino acid substitutions associated with neutralization phenotype in the human immunodeficiency virus type-1 subtype C gp120. Virology 1 12

29. LiaoHXSutherlandLLXiaSMBrockMEScearceRM 2006 Group M consensus Env oligomers induce antibodies that neutralize subtype C HIV -⁠ primary isolates. Virology 353 268 282

30. ZhangWGodillotAPWyattRSodroskiJChaikenI 2001 Antibody 17b binding at the coreceptor site weakens the kinetics of the interaction of envelope glycoprotein gp120 with CD4. Biochemistry 40 1662 1670

31. WyattRMooreJAccolaMDesjardinERobinsonJ 1995 Involvement of the V1/V2 variable loop structure in the exposure of human immunodeficiency virus type 1 gp120 epitopes induced by receptor binding. J Virol 69 5723 5733

32. GaoFScearceRMAlamSMHoraBXiaS 2009 Cross-reactive monoclonal antibodies to multiple HIV-1 subtype and SIVcpz envelope glycoproteins. Virology 394 91 98

33. CalareseDALeeHKHuangCYBestMDAstronomoRD 2005 Dissection of the carbohydrate specificity of the broadly neutralizing anti-HIV-1 antibody 2G12. Proc Natl Acad Sci U S A 102 13372 13377

34. GoEPIrunguJZhangYDalpathadoDSLiaoHX 2008 Glycosylation site-specific analysis of HIV envelope proteins (JR-FL and CON-S) reveals major differences in glycosylation site occupancy, glycoform profiles, and antigenic epitopes' accessibility. J Proteome Res 7 1660 1674

35. IrunguJGoEPZhangYDalpathadoDSLiaoHX 2008 Comparison of HPLC/ESI-FTICR MS versus MALDI-TOF/TOF MS for glycopeptide analysis of a highly glycosylated HIV envelope glycoprotein. J Am Soc Mass Spectrom 19 1209 1220

36. LiuJBartesaghiABorgniaMJSapiroGSubramaniamS 2008 Molecular architecture of native HIV-1 gp120 trimers. Nature 455 109 113

37. SandersRWVenturiMSchiffnerLKalyanaramanRKatingerH 2002 The mannose-dependent epitope for neutralizing antibody 2G12 on human immunodeficiency virus type 1 glycoprotein gp120. J Virol 76 7293 7305

38. Hager-BraunCKatingerHTomerKB 2006 The HIV-neutralizing monoclonal antibody 4E10 recognizes N-terminal sequences on the native antigen. J Immunol 176 7471 7481

39. ShihTAMeffreERoedererMNussenzweigMC 2002 Role of BCR affinity in T cell dependent antibody responses in vivo. Nat Immunol 3 570 575

40. Dal PortoJHabermanAKelsoeGShlomchikM 2002 Very low affinity B cells form germinal centers, become memory B cells, and participate in secondary immune responses when higher affinity competition is reduced. J Exp Med 195 1215 1221

41. MunshawSKeplerTB 2010 SoDA2: a Hidden Markov Model approach for identification of immunoglobulin rearrangements. Bioinformatics 26 867 872

42. FelsensteinJ 1981 Evolutionary trees from DNA sequences: a maximum likelihood approach. J Mol Evol 17 368 376

43. HartMLSaifuddinMSpearGT 2003 Glycosylation inhibitors and neuraminidase enhance human immunodeficiency virus type 1 binding and neutralization by mannose-binding lectin. J Gen Virol 84 353 360

44. WangSKLiangPHAstronomoRDHsuTLHsiehSL 2008 Targeting the carbohydrates on HIV-1: Interaction of oligomannose dendrons with human monoclonal antibody 2G12 and DC-SIGN. Proc Natl Acad Sci U S A 105 3690 3695

45. WalkerLMSimekMDPriddyFGachJSWagnerD 2010 Limited number of antibody specificities mediate broad and potent serum neutralization in selected HIV-1 infected individuals. PLoS Pathog 6 8 e1001028

46. ShenXParksRJMontefioriDCKirchherrJLKeeleBF 2009 In vivo gp41 antibodies targeting the 2F5 monoclonal antibody epitope mediate human immunodeficiency virus type 1 neutralization breadth. J Virol 83 3617 3625

47. ShenXDennisonSMLiuPGaoFJaegerF 2010 Prolonged exposure of the HIV-1 gp41 membrane proximal region with L669S substitution. Proc Natl Acad Sci U S A 107 5972 5977

48. BlishCANguyenMAOverbaughJ 2008 Enhancing exposure of HIV-1 neutralization epitopes through mutations in gp41. PLoS Med 5 1 e9

49. BenjouadAGluckmanJCRochatHMontagnierLBahraouiE 1992 Influence of carbohydrate moieties on the immunogenicity of human immunodeficiency virus type 1 recombinant gp160. J Virol 66 2473 2483

50. BhattacharyyaSRajanRESwarupaYRathoreUVermaA 2010 Design of a non-glycosylated outer domain-derived HIV-1 gp120 immunogen that binds to CD4 and induces neutralizing antibodies. J Biol Chem 285 27100 27110

51. BinleyJMBanYECrooksETEgginkDOsawaK 2010 Role of complex carbohydrates in human immunodeficiency virus type 1 infection and resistance to antibody neutralization. J Virol 84 5637 5655

52. BinleyJMWyattRDesjardinsEKwongPDHendricksonW 1998 Analysis of the interaction of antibodies with a conserved enzymatically deglycosylated core of the HIV type 1 envelope glycoprotein 120. AIDS Res Hum Retroviruses 14 191 198

53. KochMPanceraMKwongPDKolchinskyPGrundnerC 2003 Structure-based, targeted deglycosylation of HIV-1 gp120 and effects on neutralization sensitivity and antibody recognition. Virology 313 387 400

54. SagarMWuXLeeSOverbaughJ 2006 Human immunodeficiency virus type 1 V1-V2 envelope loop sequences expand and add glycosylation sites over the course of infection, and these modifications affect antibody neutralization sensitivity. J Virol 80 9586 9598

55. KongLSheppardNCStewart-JonesGBRobsonCLChenH 2010 Expression-system-dependent modulation of HIV-1 envelope glycoprotein antigenicity and immunogenicity. J Mol Biol 403 131 147

56. BusconiLLauCMTaborASUccelliniMBRuheZ 2006 DNA and RNA autoantigens as autoadjuvants. J Endotoxin Res 12 379 384

57. ShlomchikMJ 2009 Activating systemic autoimmunity: B's, T's, and tolls. Curr Opin Immunol 21 626 633

58. WuLMartinTDVazeuxRUnutmazDKewalRamaniVN 2002 Functional evaluation of DC-SIGN monoclonal antibodies reveals DC-SIGN interactions with ICAM-3 do not promote human immunodeficiency virus type 1 transmission. J Virol 76 5905 5914

59. AlamSMPaleosCALiaoHXScearceRRobinsonJ 2004 An inducible HIV type 1 gp41 HR-2 peptide-binding site on HIV type 1 envelope gp120. AIDS Res Hum Retroviruses 20 836 845

60. SchiefWRBanYEStamatatosL 2009 Challenges for structure-based HIV vaccine design. Curr Opin HIV AIDS 5 431 40

61. HuangCCTangMZhangMYMajeedSMontabanaE 2005 Structure of a V3-containing HIV-1 gp120 core. Science 310 1025 8