The Effects of Somatic Hypermutation on Neutralization and Binding in the PGT121 Family of Broadly Neutralizing HIV Antibodies

English version České info

Broadly neutralizing HIV antibodies (bnAbs) are typically highly somatically mutated, raising doubts as to whether they can be elicited by vaccination. We used 454 sequencing and designed a novel phylogenetic method to model lineage evolution of the bnAbs PGT121–134 and found a positive correlation between the level of somatic hypermutation (SHM) and the development of neutralization breadth and potency. Strikingly, putative intermediates were characterized that show approximately half the mutation level of PGT121–134 but were still capable of neutralizing roughly 40–80% of PGT121–134 sensitive viruses in a 74-virus panel at median titers between 15- and 3-fold higher than PGT121–134. Such antibodies with lower levels of SHM may be more amenable to elicitation through vaccination while still providing noteworthy coverage. Binding characterization indicated a preference of inferred intermediates for native Env binding over monomeric gp120, suggesting that the PGT121–134 lineage may have been selected for binding to native Env at some point during maturation. Analysis of glycan-dependent neutralization for inferred intermediates identified additional adjacent glycans that comprise the epitope and suggests changes in glycan dependency or recognition over the course of affinity maturation for this lineage. Finally, patterns of neutralization of inferred bnAb intermediates suggest hypotheses as to how SHM may lead to potent and broad HIV neutralization and provide important clues for immunogen design.

Vyšlo v časopise: The Effects of Somatic Hypermutation on Neutralization and Binding in the PGT121 Family of Broadly Neutralizing HIV Antibodies. PLoS Pathog 9(11): e32767. doi:10.1371/journal.ppat.1003754
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003754

Souhrn

Zdroje

1. KwongPD, MascolaJR (2012) Human antibodies that neutralize HIV-1: identification, structures, and B cell ontogenies. Immunity 37: 412–425 doi:10.1016/j.immuni.2012.08.012

2. WalkerLM, PhogatSK, Chan-HuiP-Y, WagnerD, PhungP, et al. (2009) Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science 326: 285–289 doi:10.1126/science.1178746

3. WuX, YangZ-Y, LiY, HogerkorpC-M, SchiefWR, et al. (2010) Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science 329: 856–861.

4. ZhouT, GeorgievI, WuX, YangZ-Y, DaiK, et al. (2010) Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science 329: 811–817 doi:10.1126/science.1192819

5. WalkerLM, HuberM, DooresKJ, FalkowskaE, PejchalR, et al. (2011) Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 477: 466–470.

6. WuX, ZhouT, ZhuJ, ZhangB, GeorgievI, et al. (2011) Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing. Science 333: 1593–1602 doi:10.1126/science.1207532

7. PejchalR, DooresKJ, WalkerLM, KhayatR, HuangP-S, et al. (2011) A potent and broad neutralizing antibody recognizes and penetrates the HIV glycan shield. Science 334: 1097–1103 doi:10.1126/science.1213256

8. GrayES, MadigaMC, HermanusT, MoorePL, WibmerCK, et al. (2011) The neutralization breadth of HIV-1 develops incrementally over four years and is associated with CD4+ T cell decline and high viral load during acute infection. J Virol 85: 4828–4840 doi:10.1128/JVI.00198-11

9. KleinF, DiskinR, ScheidJF, GaeblerC, MouquetH, et al. (2013) Somatic mutations of the immunoglobulin framework are generally required for broad and potent HIV-1 neutralization. Cell 153: 126–138 doi:10.1016/j.cell.2013.03.018

10. SatherDN, ArmannJ, ChingLK, MavrantoniA, SellhornG, et al. (2009) Factors associated with the development of cross-reactive neutralizing antibodies during human immunodeficiency virus type 1 infection. J Virol 83: 757–769 doi:10.1128/JVI.02036-08

11. KongL, LeeJH, DooresKJ, MurinCD, JulienJ-P, et al. (2013) Supersite of immune vulnerability on the glycosylated face of HIV-1 envelope glycoprotein gp120. Nat Struct Mol Biol 20: 796–803 doi:10.1038/nsmb.2594

12. ScheidJF, MouquetH, FeldhahnN, SeamanMS, VelinzonK, et al. (2009) Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals. Nature 458: 636–640.

13. BredenF, LepikC, LongoNS, MonteroM, LipskyPE, et al. (2011) Comparison of antibody repertoires produced by HIV-1 infection, other chronic and acute infections, and systemic autoimmune disease. PLoS ONE 6: e16857 doi:10.1371/journal.pone.0016857.t004

14. WrammertJ, KoutsonanosD, LiGM, EdupugantiS, SuiJ, et al. (2011) Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J Exp Med 208: 181–193 doi:10.1084/jem.20101352

15. CortiD, SuguitanAL, PinnaD, SilacciC, Fernandez-RodriguezBM, et al. (2010) Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine. J Clin Invest 120: 1663–1673 doi:10.1172/JCI41902

16. FrölichD, GieseckeC, MeiHE, ReiterK, DaridonC, et al. (2010) Secondary immunization generates clonally related antigen-specific plasma cells and memory B cells. J Immunol 185: 3103–3110 doi:10.4049/jimmunol.1000911

17. MoodyMA, ZhangR, WalterEB, WoodsCW, GinsburgGS, et al. (2011) H3N2 influenza infection elicits more cross-reactive and less clonally expanded anti-hemagglutinin antibodies than influenza vaccination. PLoS ONE 6: e25797 doi:10.1371/journal.pone.0025797

18. MoodyMA, YatesNL, AmosJD, DrinkerMS, EudaileyJA, et al. (2012) HIV-1 gp120 vaccine induces affinity maturation in both new and persistent antibody clonal lineages. J Virol 86: 7496–7507 doi:10.1128/JVI.00426-12

19. SundlingC, LiY, HuynhN, PoulsenC, WilsonR, et al. (2012) High-resolution definition of vaccine-elicited B cell responses against the HIV primary receptor binding site. Sci Transl Med 4: 142ra96 doi:10.1126/scitranslmed.3003752

20. LiaoHX, ChenX, MunshawS, ZhangR, MarshallDJ, et al. (2011) Initial antibodies binding to HIV-1 gp41 in acutely infected subjects are polyreactive and highly mutated. J Exp Med 208: 2237–2249 doi:10.1084/jem.20110363

21. LiaoH-X, BonsignoriM, AlamSM, McLellanJS, TomarasGD, et al. (2013) Vaccine induction of antibodies against a structurally heterogeneous site of immune pressure within HIV-1 envelope protein variable regions 1 and 2. Immunity 38: 176–186 doi:10.1016/j.immuni.2012.11.011

22. BrineyBS, WillisJR, CroweJEJ (2012) Location and length distribution of somatic hypermutation-associated DNA insertions and deletions reveals regions of antibody structural plasticity. Genes and Immunity 13: 523–529 Available: http://www.ncbi.nlm.nih.gov/pubmed/22717702.

23. PanceraM, McLellanJS, WuX, ZhuJ, ChangelaA, et al. (2012) Crystal structure of PG16 and chimeric dissection with somatically related PG9: structure-function analysis of two quaternary-specific antibodies that effectively neutralize HIV-1. J Virol 84: 8098–8110 doi:10.1128/JVI.00966-10

24. BonsignoriM, HwangK-K, ChenX, TsaoC-Y, MorrisL, et al. (2011) Analysis of a clonal lineage of HIV-1 envelope V2/V3 conformational epitope-specific broadly neutralizing antibodies and their inferred unmutated common ancestors. J Virol 85: 9998–10009 doi:10.1128/JVI.05045-11

25. MaB-J, AlamSM, GoEP, LuX, DesaireH, et al. (2011) Envelope deglycosylation enhances antigenicity of HIV-1 gp41 epitopes for both broad neutralizing antibodies and their unmutated ancestor antibodies. PLoS Pathog 7: e1002200 doi:10.1371/journal.ppat.1002200.g010

26. HootS, McGuireAT, CohenKW, StrongRK, HangartnerL, et al. (2013) Recombinant HIV envelope proteins fail to engage germline versions of anti-CD4bs bNAbs. PLoS Pathog 9: e1003106.

27. LiaoH-X, LynchR, ZhouT, GaoF, AlamSM, et al. (2013) Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature 496: 469–76 doi:10.1038/nature12053

28. WalkerLM, SokD, NishimuraY, DonauO, SadjadpourR, et al. (2011) Rapid development of glycan-specific, broad, and potent anti-HIV-1 gp120 neutralizing antibodies in an R5 SIV/HIV chimeric virus infected macaque. Proc Natl Acad Sci USA 108: 20125–20129 doi:10.1073/pnas.1117531108

29. LynchRM, TranL, LouderMK, SchmidtSD, CohenM, et al. (2012) The development of CD4 binding site antibodies during HIV-1 infection. J Virol 86: 7588–7595 doi:10.1128/JVI.00734-12

30. MoldtB, RakaszEG, SchultzN, Chan-HuiP-Y, SwiderekK, et al. (2012) Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo. Proc Natl Acad Sci USA 109: 18921–18925 doi:10.1073/pnas.1214785109

31. EdgarRC (2010) Search and clustering orders of magnitude faster than BLAST. Bioinformatics 26: 2460–2461 doi:10.1093/bioinformatics/btq461

32. ZhuJ, OfekG, YangY, ZhangB, LouderMK, et al. (2013) Mining the antibodyome for HIV-1-neutralizing antibodies with next-generation sequencing and phylogenetic pairing of heavy/light chains. Proc Natl Acad Sci USA 110: 6470–5 doi:10.1073/pnas.1219320110

33. BarakM, ZuckermanNS, EdelmanH, UngerR, MehrR (2008) IgTree: creating Immunoglobulin variable region gene lineage trees. J Immunol Methods 338: 67–74 doi:10.1016/j.jim.2008.06.006

34. HastingsWK (1970) Monte Carlo sampling methods using Markov chains and their applications. Biometrika 57: 97–109.

35. PearlJ (1982) Reverend Bayes on inference engines: A distributed hierarchical approach. Proceedings of the American Association of Artificial Intelligence National Conference on AI 133–136 http://www.aaai.org/Papers/AAAI/1982/AAAI82-032.

36. SimekMD, RidaW, PriddyFH, PungP, CarrowE, et al. (2009) Human immunodeficiency virus type 1 elite neutralizers: individuals with broad and potent neutralizing activity identified by using a high-throughput neutralization assay together with an analytical selection algorithm. J Virol 83: 7337–7348 doi:10.1128/JVI.00110-09

37. PanceraM, YangY, LouderMK, GormanJ, LuG, et al. (2013) N332-Directed broadly neutralizing antibodies use diverse modes of HIV-1 recognition: inferences from heavy-light chain complementation of function. PLoS ONE 8: e55701 doi:10.1371/journal.pone.0055701

38. JulienJ-P, 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 doi:10.1371/journal.ppat.1003342

39. MouquetH, ScharfL, EulerZ, LiuY, EdenC, et al. (2012) Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies. Proc Natl Acad Sci USA 109: E3268–E3277 doi:10.1073/pnas.1217207109

40. AlamSM, LiaoH-X, DennisonSM, JaegerF, ParksR, et al. (2011) Differential reactivity of germ line allelic variants of a broadly neutralizing HIV-1 antibody to a gp41 fusion intermediate conformation. J Virol 85: 11725–11731 doi:10.1128/JVI.05680-11

41. WalkerLM, SimekMD, PriddyF, GachJS, WagnerD, et al. (2010) A limited number of antibody specificities mediate broad and potent serum neutralization in selected HIV-1 infected individuals. PLoS Pathog 6: e1001028 doi:10.1371/journal.ppat.1001028

42. CalareseDA, ScanlanCN, ZwickMB, DeechongkitS, MimuraY, et al. (2003) Antibody domain exchange is an immunological solution to carbohydrate cluster recognition. Science 300: 2065–2071 doi:10.1126/science.1083182

43. McLellanJS, PanceraM, CarricoC, GormanJ, JulienJ-P, et al. (2011) Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9. Nature 480: 336–343 doi:10.1038/nature10696

44. DooresKJ, BurtonDR (2010) Variable loop glycan dependency of the broad and potent HIV-1-neutralizing antibodies PG9 and PG16. J Virol 84: 10510–10521.

45. EkiertDC, KashyapAK, SteelJ, RubrumA, BhabhaG, et al. (2012) Cross-neutralization of influenza A viruses mediated by a single antibody loop. Nature 489: 526–532 doi:10.1038/nature11414

46. DreyfusC, LaursenNS, KwaksT, ZuijdgeestD, KhayatR, et al. (2012) Highly conserved protective epitopes on influenza B viruses. Science 337: 1343–1348 doi:10.1126/science.1222908

47. MoirS, FauciAS (2009) B cells in HIV infection and disease. Nat Rev Immunol 9: 235–245 doi:10.1038/nri2524

48. 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.

49. KabschW (2010) Xds. Acta Crystallogr D Biol Crystallogr 66: 125–132 doi:10.1107/S0907444909047337

50. McCoyAJ, Grosse-KunstleveRW, AdamsPD, WinnMD, StoroniLC, et al. (2007) Phaser crystallographic software. J Appl Crystallogr 40: 658–674 doi:10.1107/S0021889807021206

51. AdamsPD, AfoninePV, BunkocziG, ChenVB, DavisIW, et al. (2010) PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr D Biol Crystallogr 66: 213–221 doi:10.1107/S0907444909052925

52. EmsleyP, CowtanK (2004) Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 60: 2126–2132 doi:10.1107/S0907444904019158

53. Jones E, Oliphant T, Peterson P (2001) SciPy: Open source scientific tools for Python. http://www scipy org/.

54. HunterJD (2007) Matplotlib: A 2D graphics environment. Computing in Science & Engineering 9: 90–95 doi:10.1109/mcse.2007.55

55. Ellson J, Gansner ER, Koutsofios E, North SC (2004) Graphviz and dynagraph—static and dynamic graph drawing tools. Junger M, Mutzel P, editors. Graph Drawing Software. 22 pp.