To define features of the B cell response to HIV that may be translated to vaccine development, we have isolated a panel of monoclonal antibodies (MAbs) from HIV-infected patients. These MAbs are all highly reactive to HIV envelope (Env) from multiple clades, and include gp120 and gp41 specificities. Three of the MAbs exhibit substantial homology to previously described VH1-69, VH3-30, and VH4-59 HIV broadly neutralizing antibody lineages. An inherently autoreactive VH4-34 encoded MAb was reactive to diverse Env despite its minimal mutation from germline. Its isolation is consistent with our previous observation of increased VH4-34+antibodies in HIV-infected patients. These results suggest that conserved developmental processes contribute to immunoglobulin repertoire usage and maturation in response to HIV Env and that intrinsically autoreactive VH genes, despite the absence of mutation, could serve as effective templates for maturation and development of protective antibodies. These results also bear significant implications for the development of immunogens.
Get full access to this article
View all access options for this article.
References
1.
MikellI, SatherDN, KalamsSA, AltfeldM, AlterG, and StamatatosL: Characteristics of the earliest cross-neutralizing antibody response to HIV-1. PLoS Pathog, 2011; 7:e1001251.
2.
van GilsMJ, EulerZ, SchweighardtB, WrinT, and SchuitemakerH: Prevalence of cross-reactive HIV-1-neutralizing activity in HIV-1-infected patients with rapid or slow disease progression. Aids, 2009; 23:2405–2414.
3.
WibmerCK, BhimanJN, GrayES, TumbaN, Abdool KarimSS, WilliamsonC, MorrisL, and MoorePL: Viral escape from HIV-1 neutralizing antibodies drives increased plasma neutralization breadth through sequential recognition of multiple epitopes and immunotypes. PLoS Pathog, 2013; 9:e1003738.
4.
RichmanDD, WrinT, LittleSJ, and PetropoulosCJ: Rapid evolution of the neutralizing antibody response to HIV type 1 infection. Proc Natl Acad Sci USA, 2003; 100:4144–4149.
5.
KwongPD, and MascolaJR: Human antibodies that neutralize HIV-1: identification, structures, and B cell ontogenies. Immunity, 2012; 37:412–425.
KleinF, MouquetH, DosenovicP, ScheidJF, ScharfL, and NussenzweigMC: Antibodies in HIV-1 vaccine development and therapy. Science, 2013; 341:1199–1204.
8.
KobieJJ, AlcenaDC, ZhengB, BrykP, MattiacioJL, BrewerM, LabrancheC, YoungFM, DewhurstS, MontefioriDC, RosenbergAF, FengC, JinX, KeeferMC, and SanzI: 9G4 autoreactivity is increased in HIV-infected patients and correlates with HIV broadly neutralizing serum activity. PLoS One, 2012; 7:11.
9.
RichardsonC, ChidaAS, AdlowitzD, SilverL, FoxE, JenksSA, PalmerE, WangY, Heimburg-MolinaroJ, LiQZ, MohanC, CummingsR, TiptonC, and SanzI: Molecular basis of 9G4 B cell autoreactivity in human systemic lupus erythematosus. J Immunol, 2013; 191:4926–4939.
10.
TillerT, MeffreE, YurasovS, TsuijiM, NussenzweigMC, and WardemannH: Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. J Immunol Methods, 2008; 329:112–124.
11.
MascolaJR, D'SouzaP, GilbertP, HahnBH, HaigwoodNL, MorrisL, PetropoulosCJ, PolonisVR, SarzottiM, and MontefioriDC: Recommendations for the design and use of standard virus panels to assess neutralizing antibody responses elicited by candidate human immunodeficiency virus type 1 vaccines. J Virol, 2005; 79:10103–10107.
12.
PotterKN, LiY, PascualV, WilliamsRCJr., ByresLC, SpellerbergM, StevensonFK, and CapraJD: Molecular characterization of a cross-reactive idiotope on human immunoglobulins utilizing the VH4-21 gene segment. J Exp Med, 1993; 178:1419–1428.
13.
GachJS, AchenbachCJ, ChromikovaV, BerzinsB, LambertN, LanducciG, ForthalDN, KatlamaC, JungBH, and MurphyRL: HIV-1 specific antibody titers and neutralization among chronically infected patients on long-term suppressive antiretroviral therapy (ART): a cross-sectional study. PLoS One, 2014; 9:e85371.
14.
FerreiraCB, Merino-MansillaA, LlanoA, PerezI, CrespoI, LlinasL, GarciaF, GatellJM, YusteE, and Sanchez-MerinoV: Evolution of broadly cross-reactive HIV-1-neutralizing activity: therapy-associated decline, positive association with detectable viremia, and partial restoration of B-cell subpopulations. J Virol, 2013; 87:12227–12236.
15.
Medina-RamirezM, Sanchez-MerinoV, Sanchez-PalominoS, Merino-MansillaA, FerreiraCB, PerezI, GonzalezN, AlvarezA, Alcocer-GonzalezJM, GarciaF, GatellJM, AlcamiJ, and YusteE: Broadly cross-neutralizing antibodies in HIV-1 patients with undetectable viremia. J Virol, 2011; 85:5804–5813.
16.
WuYC, KiplingD, LeongHS, MartinV, AdemokunAA, and Dunn-WaltersDK: High-throughput immunoglobulin repertoire analysis distinguishes between human IgM memory and switched memory B-cell populations. Blood, 2010; 116:1070–1078.
17.
CardosoRM, ZwickMB, StanfieldRL, KunertR, BinleyJM, KatingerH, BurtonDR, and WilsonIA: Broadly neutralizing anti-HIV antibody 4E10 recognizes a helical conformation of a highly conserved fusion-associated motif in gp41. Immunity, 2005; 22:163–173.
18.
KunertR, WolbankS, StieglerG, WeikR, and KatingerH: Characterization of molecular features, antigen-binding, and in vitro properties of IgG and IgM variants of 4E10, an anti-HIV type 1 neutralizing monoclonal antibody. AIDS Res Hum Retroviruses, 2004; 20:755–762.
19.
MorrisL, ChenX, AlamM, TomarasG, ZhangR, MarshallDJ, ChenB, ParksR, FoulgerA, JaegerF, DonathanM, BilskaM, GrayES, Abdool KarimSS, KeplerTB, WhitesidesJ, MontefioriD, MoodyMA, LiaoHX, and HaynesBF: Isolation of a human anti-HIV gp41 membrane proximal region neutralizing antibody by antigen-specific single B cell sorting. PLoS One, 2011; 6:e23532.
20.
HuangJ, OfekG, LaubL, LouderMK, Doria-RoseNA, LongoNS, ImamichiH, BailerRT, ChakrabartiB, SharmaSK, AlamSM, WangT, YangY, ZhangB, MiguelesSA, WyattR, HaynesBF, KwongPD, MascolaJR, and ConnorsM: Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature, 2012; 491:406–412.
ScharfL, WestAPJr, GaoH, LeeT, ScheidJF, NussenzweigMC, BjorkmanPJ, and DiskinR: Structural basis for HIV-1 gp120 recognition by a germ-line version of a broadly neutralizing antibody. Proc Natl Acad Sci USA, 2013; 110:6049–6054.
23.
HaynesBF, KelsoeG, HarrisonSC, and KeplerTB: B-cell-lineage immunogen design in vaccine development with HIV-1 as a case study. Nat Biotechnol, 2012; 30:423–433.
24.
KashyapAK, SteelJ, OnerAF, DillonMA, SwaleRE, WallKM, PerryKJ, FaynboymA, IlhanM, HorowitzM, HorowitzL, PaleseP, BhattRR, and LernerRA: Combinatorial antibody libraries from survivors of the Turkish H5N1 avian influenza outbreak reveal virus neutralization strategies. Proc Natl Acad Sci USA, 2008; 105:5986–5991.
25.
SuiJ, HwangWC, PerezS, WeiG, AirdD, ChenLM, SantelliE, StecB, CadwellG, AliM, WanH, MurakamiA, YammanuruA, HanT, CoxNJ, BankstonLA, DonisRO, LiddingtonRC, and MarascoWA: Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nat Struct Mol Biol, 2009; 16:265–273.
26.
ScheidJF, MouquetH, UeberheideB, DiskinR, KleinF, OliveiraTY, PietzschJ, FenyoD, AbadirA, VelinzonK, HurleyA, MyungS, BouladF, PoignardP, BurtonDR, PereyraF, HoDD, WalkerBD, SeamanMS, BjorkmanPJ, ChaitBT, and NussenzweigMC: Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding. Science, 2011; 333:1633–1637.
AlcenaDC, KobieJJ, KaminskiDA, RosenbergAF, MattiacioJL, BrewerM, DewhurstS, DykesC, JinX, KeeferMC, and SanzI: 9G4+antibodies isolated from HIV-infected patients neutralize HIV-1 and have distinct autoreactivity profiles. PLoS One, 2013; 8:e85098.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
