HIV-1 Envelope gp41 Broadly Neutralizing Antibodies: Hurdles for Vaccine Development

1. PlotkinS (2010) Correlates of protection induced by vaccination. Clin Vaccine Immunol 17 : 1055–1065.

2. WeiX, DeckerJM, WangS, HuiH, KappesJC, et al. (2003) Antibody neutralization and escape by HIV-1. Nature 422 : 307–312.

3. McElrathMJ, HaynesBF (2010) Induction of immunity to human immunodeficiency virus type-1 by vaccination. Immunity 33 : 542–554.

4. MascolaJR, HaynesBF (2013) HIV-1 neutralizing antibodies: understanding nature's pathways. Immunol Rev 254 : 225–44.

5. HessellAJ, PoignardP, HunterM, HangartnerL, TehraniDM, et al. (2009) Effective, low-titer antibody protection against low-dose repeated mucosal SHIV challenge in macaques. Nat Med 15 : 951–954.

6. HessellAJ, RakaszEG, PoignardP, HangartnerL, LanducciG, et al. (2009) Broadly neutralizing human anti-HIV antibody 2G12 is effective in protection against mucosal SHIV challenge even at low serum neutralizing titers. PLoS Pathog 5: e1000433.

7. MoldtB, RakaszEG, SchultzN, Chan-HuiPY, 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.

8. BarouchDH, WhitneyJB, MoldtB, KleinF, OliveiraTY, et al. (2013) Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature 503 : 224–228.

9. BalazsAB, ChenJ, HongCM, RaoDS, YangL, et al. (2012) Antibody-based protection against HIV infection by vectored immunoprophylaxis. Nature 481 : 81–84.

10. BonsignoriM, AlamSM, LiaoHX, VerkoczyL, TomarasGD, et al. (2012) HIV-1 antibodies from infection and vaccination: insights for guiding vaccine design. Trends Microbiol 20 : 532–539.

11. StamatatosL, MorrisL, BurtonDR, MascolaJR (2009) Neutralizing antibodies generated during natural HIV-1 infection: good news for an HIV-1 vaccine? Nature Med 15 : 866–870.

12. HaynesBF, FlemingJ, St ClairEW, KatingerH, StieglerG, et al. (2005) Cardiolipin polyspecific autoreactivity in two broadly neutralizing HIV-1 antibodies. Science 308 : 1906–1908.

13. HaynesBF, MoodyMA, VerkoczyL, KelsoeG, AlamSM (2005) Antibody polyspecificity and neutralization of HIV-1: a hypothesis. Hum Antibodies 14 : 59–67.

14. WardemannH, YurasovS, SchaeferA, YoungJW, MeffreE, et al. (2003) Predominant autoantibody production by early human B cell precursors. Science 301 : 1374–1377.

15. VerkoczyL, KelsoeG, MoodyMA, HaynesBF (2011) Role of immune mechanisms in induction of HIV-1 broadly neutralizing antibodies. Curr Opin Immunol 23 : 383–390.

16. MeffreE, MililiM, Blanco-BetancourtC, AntunesH, NussenzweigMC, et al. (2001) Immunoglobulin heavy chain expression shapes the B cell receptor repertoire in human B cell development. J Clin Invest 108 : 879–886.

17. Von BoehmerH, MelchersF (2010) Checkpoints in lymphocyte development and autoimmune disease. Nat Immunol 11 : 176–183.

18. VerkoczyL, DiazM, HollTM, OuyangY-B, Bouton-VervilleH, et al. (2010) Autoreactivity in an HIV-1 broadly reactive neutralizing antibody variable region heavy chain induces immunologic tolerance. Proc Natl Acad Sci USA 107 : 181–186.

19. VerkoczyL, ChenY, Bouton-VervilleH, ZhangJ, DiazM, et al. (2011) Rescue of HIV-1 broad neutralizing antibody-expressing B cells in 2F5 VH×VL knockin mice reveals multiple tolerance controls. J Immunol 187 : 3785–3797.

20. ChenY, ZhangJ, HwangK-K, Bouton-VervilleH, XiaS-M, et al. (2013) Common tolerance mechanisms, but distinct cross-reactivities associated with gp41 and lipids, limit production of HIV-1 broad neutralizing antibodies 2F5 and 4E10. J Immunol 191 : 1260–1275.

21. Doyle-CooperC, HudsonKE, CooperAB, OtaT, SkogP, et al. (2013) Immune Tolerance Negatively Regulates B Cells in Knock-In Mice Expressing Broadly Neutralizing HIV Antibody 4E10. J Immunol 191 : 3186–3191.

22. FintonKA, LarimoreK, LarmanHB, FriendD, CorrentiC, et al. (2013) Autoreactivity and exceptional CDR plasticity (but not unusual polyspecificity) hinder elicitation of the anti-HIV antibody 4E10. PLoS Pathog 9: e1003639.

23. AlamSM, LiaoHX, DennisonSM, JaegerF, ParksR, et al. (2011) Differential reactivity germ line allelic variants of a broadly neutralizing HIV-1 antibody to a gp41 fusion intermediate conformation. J Virol 85 : 11725–11731.

24. ZhangJ, AlamSM, Bouton-VervilleH, ChenY, NewmanA, et al. (2014) Modulation of non-neutralizing gp41 responses by an MHC-restricted TH epitope overlapping those of MPER broad neutralizing antibodies. J Immunol 192 : 1693–1706.

25. 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.

26. HaynesBF, KelsoeG, HarrisonSC, KeplerTB (2012) B-cell-lineage immunogen design in vaccine development with HIV-1 as a case study. Nat Biotech 30 : 423–433.

27. NemazeeD, BurkiK (1989) Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes. Nature 337 : 562–566.

28. EriksonJ, RadicMZ, CamperSA, HardyRR, CarmackC, et al. (1991) Expression of anti-DNA immunoglobulin transgenes in non-autoimmune mice. Nature 349 : 331–334.

29. HartleySB, CrosbieJ, BrinkR, KantorAB, BastenA, et al. (1991) Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens. Nature 353 : 765–769.

30. GoodnowCC (1992) Transgenic mice and analysis of B-cell tolerance. Ann Rev Immunol 10 : 489–518.

31. YangG, HollTM, LiuY, LiX, NicelyN, et al. (2013) Identification of autoantigens recognized by the 2F5 and 4E10 broadly neutralizing HIV-1 antibodies. J Exp Med 210 : 241–256.

32. VerkoczyL, ChenY, ZhangJ, Bouton-VervilleH, NemanA, et al. (2013) Induction of HIV-1 broad neutralizing antibodies in 2F5 knock-in mice: selection against MPER-associated autoreactivity limits T-dependent responses. J Immunol 191 : 2538–2550.

33. HuangJ, OfekG, LaubL, LouderMK, Doria-RoseNA, et al. (2012) Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature 491 : 406–412.

34. OtaT, Doyle-CooperC, CooperAB, DooresKJ, Aoki-OtaM, et al. (2013) B cells from Knock-in Mice Expressing Broadly Neutralizing HIV Antibody b12 Carry an Innocuous B Cell Receptor Responsive to HIV Vaccine Candidates. J Immunol 191 : 3179–85.

35. LiaoH-X, LynchR, ZhouZ, GaoG, AlamSM, et al. (2013) Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature 496 : 469–76.

36. OtaT, Doyle-CooperC, CooperAB, HuberM, FalkowskaE, et al. (2012) Anti-HIV B Cell Lines as Candidate Vaccine Biosensors. J Immunol 189 : 4816–4824.

37. ChenJ, LansfordR, StewartV, YoungF, AltFW (1993) RAG-2-deficient blastocyst complementation: an assay of gene function in lymphocyte development. Proc Natl Acad Sci USA 90 : 4528–4532.

38. BatistaFD, NeubergerMS (1998) Affinity Dependence of the B cell response to antigen: a threshold, a ceiling, and the importance of off-rate. Immunity 8 : 751–759.

39. KleinF, DiskinR, ScheidJF, GaeblerC, MouquetH, et al. (2013) Somatic mutations of the immunoglobulin framework are generally required for broad and potent neutralization. Cell 153 : 126–138.

40. MoorePL, GrayES, WibmerCK, BhimanJN, NonyaneM, et al. (2012) Evolution of an HIV glycan-dependent broadly neutralizing antibody epitope through immune escape. Nat Med 18 : 1688–1692.

41. 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.

42. AlamSM, MorelliM, DennisonSM, LiaoHX, ZhangR, et al. (2009) Role of HIV membrane in neutralization by two broadly neutralizing antibodies. Proc Natl Acad Sci USA 106 : 20234–20239.

43. MouquetH, ScheidJF, ZollerMJ, KrogsgaardM, OttRG, et al. (2010) Polyreactivity increases the apparaent affinity of anti-HIV antibodies by hereoligation. Science 467 : 591–595.

44. JardineJ, JulienJ-P, MenisS, OtaT, KalyuzhniyO, et al. (2013) Rational HIV immunogen design to target specific germline B cell receptors. Science 340 : 711–716.

45. McGuireAT, HootS, DreyerAM, LippyA, StuartA, et al. (2013) Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies. J Exp Med 210 : 655–663.

46. DormitzerPR, GrandiG, RappuoliR (2012) Structural vaccinology starts to deliver. Nat Rev Microbiol 10 : 807–813.