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HIV Broadly Neutralizing Antibodies: VRC01 and Beyond

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Book cover HIV Vaccines and Cure

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1075))

Abstract

Developing an effective prophylaxis HIV-1 vaccine is likely to require the elicitation of broadly neutralizing antibodies (bnAbs). As the HIV-1 envelope (Env) glycoprotein – the sole target of bnAbs – has evolved multiple mechanisms to evade antibody neutralization, the processes for bnAb generation are highly selective and time-consuming. Benefiting from antibody isolation technologies of single B cell culturing and direct single B cell sorting and cloning, a new generation of monoclonal bnAbs has been isolated since 2009, exhibiting remarkable breadths and potencies, thus breaking through a nearly 20-year-long limit of four monoclonal bnAbs with moderate breadth and potency. The discovery of a long list of monoclonal bnAbs has provided in-depth understanding of the sites of vulnerability on the HIV-1 Env and the complexity of human B cell immunology to generate such responses, thus presenting both guidance and challenges to move the Env immunogen design effort forward.

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References

  • Barre-Sinoussi F, Chermann JC, Rey F, Nugeyre MT, Chamaret S, Gruest J, Dauguet C, Axler-Blin C, Vezinet-Brun F, Rouzioux C, Rozenbaum W, Montagnier L (1983) Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220(4599):868–871

    Article  CAS  Google Scholar 

  • Bhiman JN, Anthony C, Doria-Rose NA, Karimanzira O, Schramm CA, Khoza T, Kitchin D, Botha G, Gorman J, Garrett NJ, Abdool Karim SS, Shapiro L, Williamson C, Kwong PD, Mascola JR, Morris L, Moore PL (2015) Viral variants that initiate and drive maturation of V1V2-directed HIV-1 broadly neutralizing antibodies. Nat Med 21(11):1332–1336. https://doi.org/10.1038/nm.3963

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Binley JM, Lybarger EA, Crooks ET, Seaman MS, Gray E, Davis KL, Decker JM, Wycuff D, Harris L, Hawkins N, Wood B, Nathe C, Richman D, Tomaras GD, Bibollet-Ruche F, Robinson JE, Morris L, Shaw GM, Montefiori DC, Mascola JR (2008) Profiling the specificity of neutralizing antibodies in a large panel of plasmas from patients chronically infected with human immunodeficiency virus type 1 subtypes B and C. J Virol 82(23):11651–11668. https://doi.org/10.1128/JVI.01762-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bonsignori M, Hwang KK, Chen X, Tsao CY, Morris L, Gray E, Marshall DJ, Crump JA, Kapiga SH, Sam NE, Sinangil F, Pancera M, Yongping Y, Zhang B, Zhu J, Kwong PD, O’Dell S, Mascola JR, Wu L, Nabel GJ, Phogat S, Seaman MS, Whitesides JF, Moody MA, Kelsoe G, Yang X, Sodroski J, Shaw GM, Montefiori DC, Kepler TB, Tomaras GD, Alam SM, Liao HX, Haynes BF (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(19):9998–10009. https://doi.org/10.1128/JVI.05045-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bonsignori M, Zhou T, Sheng Z, Chen L, Gao F, Joyce MG, Ozorowski G, Chuang GY, Schramm CA, Wiehe K, Alam SM, Bradley T, Gladden MA, Hwang KK, Iyengar S, Kumar A, Lu X, Luo K, Mangiapani MC, Parks RJ, Song H, Acharya P, Bailer RT, Cao A, Druz A, Georgiev IS, Kwon YD, Louder MK, Zhang B, Zheng A, Hill BJ, Kong R, Soto C, Mullikin JC, Douek DC, Montefiori DC, Moody MA, Shaw GM, Hahn BH, Kelsoe G, Hraber PT, Korber BT, Boyd SD, Fire AZ, Kepler TB, Shapiro L, Ward AB, Mascola JR, Liao HX, Kwong PD, Haynes BF (2016) Maturation pathway from germline to broad HIV-1 neutralizer of a CD4-mimic antibody. Cell 165:449. https://doi.org/10.1016/j.cell.2016.02.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buchacher A, Predl R, Strutzenberger K, Steinfellner W, Trkola A, Purtscher M, Gruber G, Tauer C, Steindl F, Jungbauer A et al (1994) Generation of human monoclonal antibodies against HIV-1 proteins; electrofusion and Epstein-Barr virus transformation for peripheral blood lymphocyte immortalization. AIDS Res Hum Retrovir 10(4):359–369. https://doi.org/10.1089/aid.1994.10.359

    Article  CAS  PubMed  Google Scholar 

  • Burton DR, Pyati J, Koduri R, Sharp SJ, Thornton GB, Parren PW, Sawyer LS, Hendry RM, Dunlop N, Nara PL et al (1994) Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody. Science 266(5187):1024–1027

    Article  CAS  Google Scholar 

  • Cale EM, Gorman J, Radakovich NA, Crooks ET, Osawa K, Tong T, Li J, Nagarajan R, Ozorowski G, Ambrozak DR, Asokan M, Bailer RT, Bennici AK, Chen X, Doria-Rose NA, Druz A, Feng Y, Joyce MG, Louder MK, O’Dell S, Oliver C, Pancera M, Connors M, Hope TJ, Kepler TB, Wyatt RT, Ward AB, Georgiev IS, Kwong PD, Mascola JR, Binley JM (2017) Virus-like particles identify an HIV V1V2 apex-binding neutralizing antibody that lacks a protruding loop. Immunity 46(5):777–791 e710. https://doi.org/10.1016/j.immuni.2017.04.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen W, Prabakaran P, Zhu Z, Feng Y, Streaker ED, Dimitrov DS (2012) Characterization of human IgG repertoires in an acute HIV-1 infection. Exp Mol Pathol 93(3):399–407. https://doi.org/10.1016/j.yexmp.2012.09.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Corti D, Langedijk JP, Hinz A, Seaman MS, Vanzetta F, Fernandez-Rodriguez BM, Silacci C, Pinna D, Jarrossay D, Balla-Jhagjhoorsingh S, Willems B, Zekveld MJ, Dreja H, O’Sullivan E, Pade C, Orkin C, Jeffs SA, Montefiori DC, Davis D, Weissenhorn W, McKnight A, Heeney JL, Sallusto F, Sattentau QJ, Weiss RA, Lanzavecchia A (2010) Analysis of memory B cell responses and isolation of novel monoclonal antibodies with neutralizing breadth from HIV-1-infected individuals. PLoS One 5(1):e8805. https://doi.org/10.1371/journal.pone.0008805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • DeKosky BJ, Ippolito GC, Deschner RP, Lavinder JJ, Wine Y, Rawlings BM, Varadarajan N, Giesecke C, Dorner T, Andrews SF, Wilson PC, Hunicke-Smith SP, Willson CG, Ellington AD, Georgiou G (2013) High-throughput sequencing of the paired human immunoglobulin heavy and light chain repertoire. Nat Biotechnol 31(2):166–169. https://doi.org/10.1038/nbt.2492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • DeKosky BJ, Kojima T, Rodin A, Charab W, Ippolito GC, Ellington AD, Georgiou G (2015) In-depth determination and analysis of the human paired heavy- and light-chain antibody repertoire. Nat Med 21(1):86–91. https://doi.org/10.1038/nm.3743

    Article  CAS  PubMed  Google Scholar 

  • Doria-Rose NA, Klein RM, Daniels MG, O’Dell S, Nason M, Lapedes A, Bhattacharya T, Migueles SA, Wyatt RT, Korber BT, Mascola JR, Connors M (2010) Breadth of human immunodeficiency virus-specific neutralizing activity in sera: clustering analysis and association with clinical variables. J Virol 84(3):1631–1636. https://doi.org/10.1128/JVI.01482-09

    Article  CAS  PubMed  Google Scholar 

  • Doria-Rose NA, Schramm CA, Gorman J, Moore PL, Bhiman JN, DeKosky BJ, Ernandes MJ, Georgiev IS, Kim HJ, Pancera M, Staupe RP, Altae-Tran HR, Bailer RT, Crooks ET, Cupo A, Druz A, Garrett NJ, Hoi KH, Kong R, Louder MK, Longo NS, McKee K, Nonyane M, O’Dell S, Roark RS, Rudicell RS, Schmidt SD, Sheward DJ, Soto C, Wibmer CK, Yang Y, Zhang Z, Mullikin JC, Binley JM, Sanders RW, Wilson IA, Moore JP, Ward AB, Georgiou G, Williamson C, Abdool Karim SS, Morris L, Kwong PD, Shapiro L, Mascola JR (2014) Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies. Nature 509(7498):55–62. https://doi.org/10.1038/nature13036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Falkowska E, Le KM, Ramos A, Doores KJ, Lee JH, Blattner C, Ramirez A, Derking R, van Gils MJ, Liang CH, McBride R, von Bredow B, Shivatare SS, Wu CY, Chan-Hui PY, Liu Y, Feizi T, Zwick MB, Koff WC, Seaman MS, Swiderek K, Moore JP, Evans D, Paulson JC, Wong CH, Ward AB, Wilson IA, Sanders RW, Poignard P, Burton DR (2014) Broadly neutralizing HIV antibodies define a glycan-dependent epitope on the prefusion conformation of gp41 on cleaved envelope trimers. Immunity 40(5):657–668. https://doi.org/10.1016/j.immuni.2014.04.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Freund NT, Horwitz JA, Nogueira L, Sievers SA, Scharf L, Scheid JF, Gazumyan A, Liu C, Velinzon K, Goldenthal A, Sanders RW, Moore JP, Bjorkman PJ, Seaman MS, Walker BD, Klein F, Nussenzweig MC (2015) A new glycan-dependent CD4-binding site neutralizing antibody exerts pressure on HIV-1 in vivo. PLoS Pathog 11(10):e1005238. https://doi.org/10.1371/journal.ppat.1005238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gallo RC, Sarin PS, Gelmann EP, Robert-Guroff M, Richardson E, Kalyanaraman VS, Mann D, Sidhu GD, Stahl RE, Zolla-Pazner S, Leibowitch J, Popovic M (1983) Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS). Science 220(4599):865–867

    Article  CAS  Google Scholar 

  • Gallo RC, Salahuddin SZ, Popovic M, Shearer GM, Kaplan M, Haynes BF, Palker TJ, Redfield R, Oleske J, Safai B et al (1984) Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS. Science 224(4648):500–503

    Article  CAS  Google Scholar 

  • Gao F, Bonsignori M, Liao HX, Kumar A, Xia SM, Lu X, Cai F, Hwang KK, Song H, Zhou T, Lynch RM, Alam SM, Moody MA, Ferrari G, Berrong M, Kelsoe G, Shaw GM, Hahn BH, Montefiori DC, Kamanga G, Cohen MS, Hraber P, Kwong PD, Korber BT, Mascola JR, Kepler TB, Haynes BF (2014) Cooperation of B cell lineages in induction of HIV-1-broadly neutralizing antibodies. Cell 158(3):481–491. https://doi.org/10.1016/j.cell.2014.06.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Georgiev IS, Doria-Rose NA, Zhou T, Kwon YD, Staupe RP, Moquin S, Chuang GY, Louder MK, Schmidt SD, Altae-Tran HR, Bailer RT, McKee K, Nason M, O’Dell S, Ofek G, Pancera M, Srivatsan S, Shapiro L, Connors M, Migueles SA, Morris L, Nishimura Y, Martin MA, Mascola JR, Kwong PD (2013) Delineating antibody recognition in polyclonal sera from patterns of HIV-1 isolate neutralization. Science 340(6133):751–756. https://doi.org/10.1126/science.1233989

    Article  CAS  PubMed  Google Scholar 

  • Gray ES, Taylor N, Wycuff D, Moore PL, Tomaras GD, Wibmer CK, Puren A, DeCamp A, Gilbert PB, Wood B, Montefiori DC, Binley JM, Shaw GM, Haynes BF, Mascola JR, Morris L (2009) Antibody specificities associated with neutralization breadth in plasma from human immunodeficiency virus type 1 subtype C-infected blood donors. J Virol 83(17):8925–8937. https://doi.org/10.1128/JVI.00758-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He L, Sok D, Azadnia P, Hsueh J, Landais E, Simek M, Koff WC, Poignard P, Burton DR, Zhu J (2014) Toward a more accurate view of human B-cell repertoire by next-generation sequencing, unbiased repertoire capture and single-molecule barcoding. Sci Rep 4:6778. https://doi.org/10.1038/srep06778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hraber P, Seaman MS, Bailer RT, Mascola JR, Montefiori DC, Korber BT (2014) Prevalence of broadly neutralizing antibody responses during chronic HIV-1 infection. AIDS 28(2):163–169. https://doi.org/10.1097/QAD.0000000000000106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu JK, Crampton JC, Cupo A, Ketas T, van Gils MJ, Sliepen K, de Taeye SW, Sok D, Ozorowski G, Deresa I, Stanfield R, Ward AB, Burton DR, Klasse PJ, Sanders RW, Moore JP, Crotty S (2015) Murine antibody responses to cleaved soluble HIV-1 envelope trimers are highly restricted in specificity. J Virol 89(20):10383–10398. https://doi.org/10.1128/JVI.01653-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang J, Ofek G, Laub L, Louder MK, Doria-Rose NA, Longo NS, Imamichi H, Bailer RT, Chakrabarti B, Sharma SK, Alam SM, Wang T, Yang Y, Zhang B, Migueles SA, Wyatt R, Haynes BF, Kwong PD, Mascola JR, Connors M (2012) Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature 491(7424):406–412. https://doi.org/10.1038/nature11544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang J, Kang BH, Pancera M, Lee JH, Tong T, Feng Y, Imamichi H, Georgiev IS, Chuang GY, Druz A, Doria-Rose NA, Laub L, Sliepen K, van Gils MJ, de la Pena AT, Derking R, Klasse PJ, Migueles SA, Bailer RT, Alam M, Pugach P, Haynes BF, Wyatt RT, Sanders RW, Binley JM, Ward AB, Mascola JR, Kwong PD, Connors M (2014) Broad and potent HIV-1 neutralization by a human antibody that binds the gp41-gp120 interface. Nature 515(7525):138–142. https://doi.org/10.1038/nature13601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang J, Kang BH, Ishida E, Zhou T, Griesman T, Sheng Z, Wu F, Doria-Rose NA, Zhang B, McKee K, O’Dell S, Chuang GY, Druz A, Georgiev IS, Schramm CA, Zheng A, Joyce MG, Asokan M, Ransier A, Darko S, Migueles SA, Bailer RT, Louder MK, Alam SM, Parks R, Kelsoe G, Von Holle T, Haynes BF, Douek DC, Hirsch V, Seaman MS, Shapiro L, Mascola JR, Kwong PD, Connors M (2016) Identification of a CD4-binding-site antibody to HIV that evolved near-pan neutralization breadth. Immunity 45(5):1108–1121. https://doi.org/10.1016/j.immuni.2016.10.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jardine JG, Kulp DW, Havenar-Daughton C, Sarkar A, Briney B, Sok D, Sesterhenn F, Ereno-Orbea J, Kalyuzhniy O, Deresa I, Hu X, Spencer S, Jones M, Georgeson E, Adachi Y, Kubitz M, deCamp AC, Julien JP, Wilson IA, Burton DR, Crotty S, Schief WR (2016) HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen. Science 351(6280):1458–1463. https://doi.org/10.1126/science.aad9195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jia M, Lu H, Markowitz M, Cheng-Mayer C, Wu X (2016) Development of broadly neutralizing antibodies and their mapping by monomeric gp120 in human immunodeficiency virus type 1-infected humans and simian-human immunodeficiency virus SHIVSF162P3N-infected macaques. J Virol 90(8):4017–4031. https://doi.org/10.1128/JVI.02898-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klein F, Gaebler C, Mouquet H, Sather DN, Lehmann C, Scheid JF, Kraft Z, Liu Y, Pietzsch J, Hurley A, Poignard P, Feizi T, Morris L, Walker BD, Fatkenheuer G, Seaman MS, Stamatatos L, Nussenzweig MC (2012) Broad neutralization by a combination of antibodies recognizing the CD4 binding site and a new conformational epitope on the HIV-1 envelope protein. J Exp Med 209(8):1469–1479. https://doi.org/10.1084/jem.20120423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kong L, Ju B, Chen Y, He L, Ren L, Liu J, Hong K, Su B, Wang Z, Ozorowski G, Ji X, Hua Y, Deller MC, Hao Y, Feng Y, Garces F, Wilson R, Dai K, O’Dell S, McKee K, Mascola JR, Ward AB, Wyatt RT, Li Y, Wilson IA, Zhu J, Shao Y (2016a) Key gp120 Glycans pose roadblocks to the rapid development of VRC01-class antibodies in an HIV-1-infected Chinese donor. Immunity 44:939. https://doi.org/10.1016/j.immuni.2016.03.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kong R, Xu K, Zhou T, Acharya P, Lemmin T, Liu K, Ozorowski G, Soto C, Taft JD, Bailer RT, Cale EM, Chen L, Choi CW, Chuang GY, Doria-Rose NA, Druz A, Georgiev IS, Gorman J, Huang J, Joyce MG, Louder MK, Ma X, McKee K, O’Dell S, Pancera M, Yang Y, Blanchard SC, Mothes W, Burton DR, Koff WC, Connors M, Ward AB, Kwong PD, Mascola JR (2016b) Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody. Science 352(6287):828–833. https://doi.org/10.1126/science.aae0474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kovacs JA, Vasudevachari MB, Easter M, Davey RT, Falloon J, Polis MA, Metcalf JA, Salzman N, Baseler M, Smith GE et al (1993) Induction of humoral and cell-mediated anti-human immunodeficiency virus (HIV) responses in HIV sero-negative volunteers by immunization with recombinant gp160. J Clin Invest 92(2):919–928. https://doi.org/10.1172/JCI116667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kwong PD, Mascola JR (2012) Human antibodies that neutralize HIV-1: identification, structures, and B cell ontogenies. Immunity 37(3):412–425. https://doi.org/10.1016/j.immuni.2012.08.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, Hendrickson WA (1998) Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 393(6686):648–659. https://doi.org/10.1038/31405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kwong PD, Mascola JR, Nabel GJ (2013) Broadly neutralizing antibodies and the search for an HIV-1 vaccine: the end of the beginning. Nat Rev Immunol 13(9):693–701. https://doi.org/10.1038/nri3516

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Migueles SA, Welcher B, Svehla K, Phogat A, Louder MK, Wu X, Shaw GM, Connors M, Wyatt RT, Mascola JR (2007) Broad HIV-1 neutralization mediated by CD4-binding site antibodies. Nat Med 13(9):1032–1034. https://doi.org/10.1038/nm1624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Y, O’Dell S, Walker LM, Wu X, Guenaga J, Feng Y, Schmidt SD, McKee K, Louder MK, Ledgerwood JE, Graham BS, Haynes BF, Burton DR, Wyatt RT, Mascola JR (2011) Mechanism of neutralization by the broadly neutralizing HIV-1 monoclonal antibody VRC01. J Virol 85(17):8954–8967. https://doi.org/10.1128/JVI.00754-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liao HX, Lynch R, Zhou T, Gao F, Alam SM, Boyd SD, Fire AZ, Roskin KM, Schramm CA, Zhang Z, Zhu J, Shapiro L, Mullikin JC, Gnanakaran S, Hraber P, Wiehe K, Kelsoe G, Yang G, Xia SM, Montefiori DC, Parks R, Lloyd KE, Scearce RM, Soderberg KA, Cohen M, Kamanga G, Louder MK, Tran LM, Chen Y, Cai F, Chen S, Moquin S, Du X, Joyce MG, Srivatsan S, Zhang B, Zheng A, Shaw GM, Hahn BH, Kepler TB, Korber BT, Kwong PD, Mascola JR, Haynes BF (2013) Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature 496(7446):469–476. https://doi.org/10.1038/nature12053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • MacLeod DT, Choi NM, Briney B, Garces F, Ver LS, Landais E, Murrell B, Wrin T, Kilembe W, Liang CH, Ramos A, Bian CB, Wickramasinghe L, Kong L, Eren K, Wu CY, Wong CH, Kosakovsky Pond SL, Wilson IA, Burton DR, Poignard P (2016) Early antibody lineage diversification and independent limb maturation lead to broad HIV-1 neutralization targeting the Env high-mannose patch. Immunity 44(5):1215–1226. https://doi.org/10.1016/j.immuni.2016.04.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mascola JR, Haynes BF (2013) HIV-1 neutralizing antibodies: understanding nature’s pathways. Immunol Rev 254(1):225–244. https://doi.org/10.1111/imr.12075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mascola JR, Louwagie J, McCutchan FE, Fischer CL, Hegerich PA, Wagner KF, Fowler AK, McNeil JG, Burke DS (1994) Two antigenically distinct subtypes of human immunodeficiency virus type 1: viral genotype predicts neutralization serotype. J Infect Dis 169(1):48–54

    Article  CAS  Google Scholar 

  • Mascola JR, Lewis MG, Stiegler G, Harris D, VanCott TC, Hayes D, Louder MK, Brown CR, Sapan CV, Frankel SS, Lu Y, Robb ML, Katinger H, Birx DL (1999) Protection of macaques against pathogenic simian/human immunodeficiency virus 89.6PD by passive transfer of neutralizing antibodies. J Virol 73(5):4009–4018

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mascola JR, Stiegler G, VanCott TC, Katinger H, Carpenter CB, Hanson CE, Beary H, Hayes D, Frankel SS, Birx DL, Lewis MG (2000) Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies. Nat Med 6(2):207–210. https://doi.org/10.1038/72318

    Article  CAS  PubMed  Google Scholar 

  • Moore JP, Sodroski J (1996) Antibody cross-competition analysis of the human immunodeficiency virus type 1 gp120 exterior envelope glycoprotein. J Virol 70(3):1863–1872

    CAS  PubMed  PubMed Central  Google Scholar 

  • Moore JP, Cao Y, Qing L, Sattentau QJ, Pyati J, Koduri R, Robinson J, Barbas CF 3rd, Burton DR, Ho DD (1995) Primary isolates of human immunodeficiency virus type 1 are relatively resistant to neutralization by monoclonal antibodies to gp120, and their neutralization is not predicted by studies with monomeric gp120. J Virol 69(1):101–109

    CAS  PubMed  PubMed Central  Google Scholar 

  • Moore PL, Gray ES, Morris L (2009) Specificity of the autologous neutralizing antibody response. Curr Opin HIV AIDS 4(5):358–363. https://doi.org/10.1097/COH.0b013e32832ea7e8

    Article  PubMed  PubMed Central  Google Scholar 

  • Muster T, Steindl F, Purtscher M, Trkola A, Klima A, Himmler G, Ruker F, Katinger H (1993) A conserved neutralizing epitope on gp41 of human immunodeficiency virus type 1. J Virol 67(11):6642–6647

    CAS  PubMed  PubMed Central  Google Scholar 

  • Navis M, Tran K, Bale S, Phad GE, Guenaga J, Wilson R, Soldemo M, McKee K, Sundling C, Mascola J, Li Y, Wyatt RT, Karlsson Hedestam GB (2014) HIV-1 receptor binding site-directed antibodies using a VH1-2 gene segment orthologue are activated by Env trimer immunization. PLoS Pathog 10(8):e1004337. https://doi.org/10.1371/journal.ppat.1004337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parren PW, Wang M, Trkola A, Binley JM, Purtscher M, Katinger H, Moore JP, Burton DR (1998) Antibody neutralization-resistant primary isolates of human immunodeficiency virus type 1. J Virol 72(12):10270–10274

    CAS  PubMed  PubMed Central  Google Scholar 

  • Scheid JF, Mouquet H, Feldhahn N, Seaman MS, Velinzon K, Pietzsch J, Ott RG, Anthony RM, Zebroski H, Hurley A, Phogat A, Chakrabarti B, Li Y, Connors M, Pereyra F, Walker BD, Wardemann H, Ho D, Wyatt RT, Mascola JR, Ravetch JV, Nussenzweig MC (2009) Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals. Nature 458(7238):636–640. https://doi.org/10.1038/nature07930

    Article  CAS  PubMed  Google Scholar 

  • Scheid JF, Mouquet H, Ueberheide B, Diskin R, Klein F, Oliveira TY, Pietzsch J, Fenyo D, Abadir A, Velinzon K, Hurley A, Myung S, Boulad F, Poignard P, Burton DR, Pereyra F, Ho DD, Walker BD, Seaman MS, Bjorkman PJ, Chait BT, Nussenzweig MC (2011) Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding. Science 333(6049):1633–1637. https://doi.org/10.1126/science.1207227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schwartz DH, Gorse G, Clements ML, Belshe R, Izu A, Duliege AM, Berman P, Twaddell T, Stablein D, Sposto R et al (1993) Induction of HIV-1-neutralising and syncytium-inhibiting antibodies in uninfected recipients of HIV-1IIIB rgp120 subunit vaccine. Lancet 342(8863):69–73

    Article  CAS  Google Scholar 

  • Seaman MS, Janes H, Hawkins N, Grandpre LE, Devoy C, Giri A, Coffey RT, Harris L, Wood B, Daniels MG, Bhattacharya T, Lapedes A, Polonis VR, McCutchan FE, Gilbert PB, Self SG, Korber BT, Montefiori DC, Mascola JR (2010) Tiered categorization of a diverse panel of HIV-1 Env pseudoviruses for assessment of neutralizing antibodies. J Virol 84(3):1439–1452. https://doi.org/10.1128/JVI.02108-09

    Article  CAS  PubMed  Google Scholar 

  • Shingai M, Donau OK, Schmidt SD, Gautam R, Plishka RJ, Buckler-White A, Sadjadpour R, Lee WR, LaBranche CC, Montefiori DC, Mascola JR, Nishimura Y, Martin MA (2012) Most rhesus macaques infected with the CCR5-tropic SHIV(AD8) generate cross-reactive antibodies that neutralize multiple HIV-1 strains. Proc Natl Acad Sci U S A 109(48):19769–19774. https://doi.org/10.1073/pnas.1217443109

    Article  PubMed  PubMed Central  Google Scholar 

  • Simek MD, Rida W, Priddy FH, Pung P, Carrow E, Laufer DS, Lehrman JK, Boaz M, Tarragona-Fiol T, Miiro G, Birungi J, Pozniak A, McPhee DA, Manigart O, Karita E, Inwoley A, Jaoko W, Dehovitz J, Bekker LG, Pitisuttithum P, Paris R, Walker LM, Poignard P, Wrin T, Fast PE, Burton DR, Koff WC (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(14):7337–7348. https://doi.org/10.1128/JVI.00110-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sundling C, Li Y, Huynh N, Poulsen C, Wilson R, O’Dell S, Feng Y, Mascola JR, Wyatt RT, Karlsson Hedestam GB (2012) High-resolution definition of vaccine-elicited B cell responses against the HIV primary receptor binding site. Sci Transl Med 4(142):142ra196. https://doi.org/10.1126/scitranslmed.3003752

    Article  CAS  Google Scholar 

  • Sundling C, Zhang Z, Phad GE, Sheng Z, Wang Y, Mascola JR, Li Y, Wyatt RT, Shapiro L, Karlsson Hedestam GB (2014) Single-cell and deep sequencing of IgG-switched macaque B cells reveal a diverse Ig repertoire following immunization. J Immunol 192(8):3637–3644. https://doi.org/10.4049/jimmunol.1303334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tiller T, Meffre E, Yurasov S, Tsuiji M, Nussenzweig MC, Wardemann H (2008) Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. J Immunol Methods 329(1–2):112–124. https://doi.org/10.1016/j.jim.2007.09.017

    Article  CAS  PubMed  Google Scholar 

  • Trkola A, Pomales AB, Yuan H, Korber B, Maddon PJ, Allaway GP, Katinger H, Barbas CF, 3rd, Burton DR, Ho DD, et al. (1995) Cross-clade neutralization of primary isolates of human immunodeficiency virus type 1 by human monoclonal antibodies and tetrameric CD4-IgG. J Virol 69 (11):6609–6617

    Google Scholar 

  • Trkola A, Kuster H, Rusert P, Joos B, Fischer M, Leemann C, Manrique A, Huber M, Rehr M, Oxenius A, Weber R, Stiegler G, Vcelar B, Katinger H, Aceto L, Gunthard HF (2005) Delay of HIV-1 rebound after cessation of antiretroviral therapy through passive transfer of human neutralizing antibodies. Nat Med 11(6):615–622. https://doi.org/10.1038/nm1244

    Article  CAS  PubMed  Google Scholar 

  • van Gils MJ, van den Kerkhof TL, Ozorowski G, Cottrell CA, Sok D, Pauthner M, Pallesen J, de Val N, Yasmeen A, de Taeye SW, Schorcht A, Gumbs S, Johanna I, Saye-Francisco K, Liang CH, Landais E, Nie X, Pritchard LK, Crispin M, Kelsoe G, Wilson IA, Schuitemaker H, Klasse PJ, Moore JP, Burton DR, Ward AB, Sanders RW (2016) An HIV-1 antibody from an elite neutralizer implicates the fusion peptide as a site of vulnerability. Nat Microbiol 2:16199. https://doi.org/10.1038/nmicrobiol.2016.199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Walker LM, Phogat SK, Chan-Hui PY, Wagner D, Phung P, Goss JL, Wrin T, Simek MD, Fling S, Mitcham JL, Lehrman JK, Priddy FH, Olsen OA, Frey SM, Hammond PW, Kaminsky S, Zamb T, Moyle M, Koff WC, Poignard P, Burton DR (2009) Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science 326(5950):285–289. https://doi.org/10.1126/science.1178746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Walker LM, Simek MD, Priddy F, Gach JS, Wagner D, Zwick MB, Phogat SK, Poignard P, Burton DR (2010) A limited number of antibody specificities mediate broad and potent serum neutralization in selected HIV-1 infected individuals. PLoS Pathog 6(8):e1001028. https://doi.org/10.1371/journal.ppat.1001028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Walker LM, Huber M, Doores KJ, Falkowska E, Pejchal R, Julien JP, Wang SK, Ramos A, Chan-Hui PY, Moyle M, Mitcham JL, Hammond PW, Olsen OA, Phung P, Fling S, Wong CH, Phogat S, Wrin T, Simek MD, Koff WC, Wilson IA, Burton DR, Poignard P (2011a) Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 477(7365):466–470. https://doi.org/10.1038/nature10373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Walker LM, Sok D, Nishimura Y, Donau O, Sadjadpour R, Gautam R, Shingai M, Pejchal R, Ramos A, Simek MD, Geng Y, Wilson IA, Poignard P, Martin MA, Burton DR (2011b) 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 U S A 108(50):20125–20129. https://doi.org/10.1073/pnas.1117531108

    Article  PubMed  PubMed Central  Google Scholar 

  • Wei X, Decker JM, Wang S, Hui H, Kappes JC, Wu X, Salazar-Gonzalez JF, Salazar MG, Kilby JM, Saag MS, Komarova NL, Nowak MA, Hahn BH, Kwong PD, Shaw GM (2003) Antibody neutralization and escape by HIV-1. Nature 422(6929):307–312. https://doi.org/10.1038/nature01470

    Article  CAS  PubMed  Google Scholar 

  • West AP Jr, Diskin R, Nussenzweig MC, Bjorkman PJ (2012) Structural basis for germ-line gene usage of a potent class of antibodies targeting the CD4-binding site of HIV-1 gp120. Proc Natl Acad Sci U S A 109(30):E2083–E2090. https://doi.org/10.1073/pnas.1208984109

    Article  PubMed  PubMed Central  Google Scholar 

  • Wibmer CK, Gorman J, Ozorowski G, Bhiman JN, Sheward DJ, Elliott DH, Rouelle J, Smira A, Joyce MG, Ndabambi N, Druz A, Asokan M, Burton DR, Connors M, Abdool Karim SS, Mascola JR, Robinson JE, Ward AB, Williamson C, Kwong PD, Morris L, Moore PL (2017) Structure and recognition of a novel HIV-1 gp120-gp41 Interface antibody that caused MPER exposure through viral escape. PLoS Pathog 13(1):e1006074. https://doi.org/10.1371/journal.ppat.1006074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wrammert J, Smith K, Miller J, Langley WA, Kokko K, Larsen C, Zheng NY, Mays I, Garman L, Helms C, James J, Air GM, Capra JD, Ahmed R, Wilson PC (2008) Rapid cloning of high-affinity human monoclonal antibodies against influenza virus. Nature 453(7195):667–671. https://doi.org/10.1038/nature06890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu X, Kong XP (2016) Antigenic landscape of the HIV-1 envelope and new immunological concepts defined by HIV-1 broadly neutralizing antibodies. Curr Opin Immunol 42:56–64. https://doi.org/10.1016/j.coi.2016.05.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu X, Zhou T, O’Dell S, Wyatt RT, Kwong PD, Mascola JR (2009) Mechanism of human immunodeficiency virus type 1 resistance to monoclonal antibody B12 that effectively targets the site of CD4 attachment. J Virol 83(21):10892–10907. https://doi.org/10.1128/JVI.01142-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu X, Yang ZY, Li Y, Hogerkorp CM, Schief WR, Seaman MS, Zhou T, Schmidt SD, Wu L, Xu L, Longo NS, McKee K, O’Dell S, Louder MK, Wycuff DL, Feng Y, Nason M, Doria-Rose N, Connors M, Kwong PD, Roederer M, Wyatt RT, Nabel GJ, Mascola JR (2010) Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science 329(5993):856–861. https://doi.org/10.1126/science.1187659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu X, Zhou T, Zhu J, Zhang B, Georgiev I, Wang C, Chen X, Longo NS, Louder M, McKee K, O’Dell S, Perfetto S, Schmidt SD, Shi W, Wu L, Yang Y, Yang ZY, Yang Z, Zhang Z, Bonsignori M, Crump JA, Kapiga SH, Sam NE, Haynes BF, Simek M, Burton DR, Koff WC, Doria-Rose NA, Connors M, Mullikin JC, Nabel GJ, Roederer M, Shapiro L, Kwong PD, Mascola JR (2011) Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing. Science 333(6049):1593–1602. https://doi.org/10.1126/science.1207532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu X, Zhang Z, Schramm CA, Joyce MG, Kwon YD, Zhou T, Sheng Z, Zhang B, O’Dell S, McKee K, Georgiev IS, Chuang GY, Longo NS, Lynch RM, Saunders KO, Soto C, Srivatsan S, Yang Y, Bailer RT, Louder MK, Mullikin JC, Connors M, Kwong PD, Mascola JR, Shapiro L (2015) Maturation and diversity of the VRC01-antibody lineage over 15 years of chronic HIV-1 infection. Cell 161(3):470–485. https://doi.org/10.1016/j.cell.2015.03.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiao M, Prabakaran P, Chen W, Kessing B, Dimitrov DS (2013) Deep sequencing and Circos analyses of antibody libraries reveal antigen-driven selection of Ig VH genes during HIV-1 infection. Exp Mol Pathol 95(3):357–363. https://doi.org/10.1016/j.yexmp.2013.10.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yin L, Hou W, Liu L, Cai Y, Wallet MA, Gardner BP, Chang K, Lowe AC, Rodriguez CA, Sriaroon P, Farmerie WG, Sleasman JW, Goodenow MM (2013) IgM repertoire biodiversity is reduced in HIV-1 infection and systemic lupus erythematosus. Front Immunol 4:373. https://doi.org/10.3389/fimmu.2013.00373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Yuan T, Li J, Xu J, Shao Y, Chen Z, Zhang MY (2013) The potential of the human immune system to develop broadly neutralizing HIV-1 antibodies: implications for vaccine development. AIDS 27(16):2529–2539. https://doi.org/10.1097/QAD.0000000000000015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou T, Xu L, Dey B, Hessell AJ, Van Ryk D, Xiang SH, Yang X, Zhang MY, Zwick MB, Arthos J, Burton DR, Dimitrov DS, Sodroski J, Wyatt R, Nabel GJ, Kwong PD (2007) Structural definition of a conserved neutralization epitope on HIV-1 gp120. Nature 445(7129):732–737. https://doi.org/10.1038/nature05580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou T, Georgiev I, Wu X, Yang ZY, Dai K, Finzi A, Kwon YD, Scheid JF, Shi W, Xu L, Yang Y, Zhu J, Nussenzweig MC, Sodroski J, Shapiro L, Nabel GJ, Mascola JR, Kwong PD (2010) Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science 329(5993):811–817. https://doi.org/10.1126/science.1192819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou T, Zhu J, Wu X, Moquin S, Zhang B, Acharya P, Georgiev IS, Altae-Tran HR, Chuang GY, Joyce MG, Kwon YD, Longo NS, Louder MK, Luongo T, McKee K, Schramm CA, Skinner J, Yang Y, Yang Z, Zhang Z, Zheng A, Bonsignori M, Haynes BF, Scheid JF, Nussenzweig MC, Simek M, Burton DR, Koff WC, Mullikin JC, Connors M, Shapiro L, Nabel GJ, Mascola JR, Kwong PD (2013) Multidonor analysis reveals structural elements, genetic determinants, and maturation pathway for HIV-1 neutralization by VRC01-class antibodies. Immunity 39(2):245–258. https://doi.org/10.1016/j.immuni.2013.04.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou T, Lynch RM, Chen L, Acharya P, Wu X, Doria-Rose NA, Joyce MG, Lingwood D, Soto C, Bailer RT, Ernandes MJ, Kong R, Longo NS, Louder MK, McKee K, O’Dell S, Schmidt SD, Tran L, Yang Z, Druz A, Luongo TS, Moquin S, Srivatsan S, Yang Y, Zhang B, Zheng A, Pancera M, Kirys T, Georgiev IS, Gindin T, Peng HP, Yang AS, Mullikin JC, Gray MD, Stamatatos L, Burton DR, Koff WC, Cohen MS, Haynes BF, Casazza JP, Connors M, Corti D, Lanzavecchia A, Sattentau QJ, Weiss RA, West AP, Jr., Bjorkman PJ, Scheid JF, Nussenzweig MC, Shapiro L, Mascola JR, Kwong PD (2015) Structural repertoire of HIV-1-neutralizing antibodies targeting the CD4 supersite in 14 donors. Cell 161 (6):1280–1292. doi:https://doi.org/10.1016/j.cell.2015.05.007

    Article  CAS  Google Scholar 

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Acknowledgments

Xueling Wu and her laboratory are funded by internal funds from the Aaron Diamond AIDS Research Center and by research grants R01AI114380 and R01AI122593 from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), USA.

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Wu, X. (2018). HIV Broadly Neutralizing Antibodies: VRC01 and Beyond. In: Zhang, L., Lewin, S. (eds) HIV Vaccines and Cure . Advances in Experimental Medicine and Biology, vol 1075. Springer, Singapore. https://doi.org/10.1007/978-981-13-0484-2_3

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