Incomplete Neutralization and Deviation from Sigmoidal Neutralization Curves for HIV Broadly Neutralizing Monoclonal Antibodies

PLoS Pathogens

Volumn 11, Issue 8, 2015, Pages

  McCoy, Laura E ^a   Falkowska, Emilia ^a,b   Doores, Katie J ^c   Le, Khoa ^a   Sok, Devin ^a   van Gils, Marit J ^d   Euler, Zelda ^d   Burger, Judith A ^d   Seaman, Michael S ^e   Sanders, Rogier W ^d   Schuitemaker, Hanneke ^d   Poignard, Pascal ^a   Wrin, Terri ^f   Burton, Dennis R ^a,b  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

^b MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

^c GUY S HOSPITAL   (United Kingdom)

^d UNIVERSITY OF AMSTERDAM   (Netherlands)

^e BETH ISRAEL DEACONESS MEDICAL CENTER   (United States)

^f MONOGRAM BIOSCIENCES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BROADLY NEUTRALIZING HIV MONOCLONAL ANTIBODY; CHEMOKINE RECEPTOR CCR5; CHEMOKINE RECEPTOR CXCR4; ENVELOPE GLYCOPROTEIN; EPITOPE; GLYCOPROTEIN; GLYCOPROTEIN 41; MONOCLONAL ANTIBODY; UNCLASSIFIED DRUG; HUMAN IMMUNODEFICIENCY VIRUS ANTIBODY; NEUTRALIZING ANTIBODY;

ANTIBODY BLOOD LEVEL; ANTIBODY COMBINING SITE; ARTICLE; BLOOD ANALYSIS; CD4 T LYMPHOCYTE; ENZYME LINKED IMMUNOSORBENT ASSAY; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS 1; MEMBRANE PROXIMAL EXTERNAL REGION; NONHUMAN; NORMAL HUMAN; PERIPHERAL BLOOD MONONUCLEAR CELL; VIRUS ENVELOPE; VIRUS NEUTRALIZATION; HEK293 CELL LINE; IMMUNOLOGY; SERODIAGNOSIS;

ANTIBODIES, MONOCLONAL; ANTIBODIES, NEUTRALIZING; HEK293 CELLS; HIV ANTIBODIES; HIV-1; HUMANS; NEUTRALIZATION TESTS;

EID: 84940763233     PISSN: 15537366     EISSN: 15537374     Source Type: Journal    
DOI: 10.1371/journal.ppat.1005110     Document Type: Article

References (65)

1. Leonard CK, Spellman MW, Riddle L, Harris RJ, Thomas JN, et al. (1990) Assignment of intrachain disulfide bonds and characterization of potential glycosylation sites of the type 1 recombinant human immunodeficiency virus envelope glycoprotein (gp120) expressed in Chinese hamster ovary cells. J Biol Chem 265: 10373–10382. 2355006
2. Lee WR, Yu XF, Syu WJ, Essex M, Lee TH, (1992) Mutational analysis of conserved N-linked glycosylation sites of human immunodeficiency virus type 1 gp41. J Virol 66: 1799–1803. 1738209
3. Burton DR, Poignard P, Stanfield RL, Wilson IA, (2012) Broadly neutralizing antibodies present new prospects to counter highly antigenically diverse viruses. Science 337: 183–186. doi: 10.1126/science.1225416 22798606
4. West AP, Jr.Scharf L, Scheid JF, Klein F, Bjorkman PJ, et al. (2014) Structural insights on the role of antibodies in HIV-1 vaccine and therapy. Cell 156: 633–648. doi: 10.1016/j.cell.2014.01.052 24529371
5. Mascola JR, Haynes BF, (2013) HIV-1 neutralizing antibodies: understanding nature's pathways. Immunol Rev 254: 225–244. doi: 10.1111/imr.12075 23772623
6. Kwong PD, Mascola JR, (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 22999947
7. Julien JP, Cupo A, Sok D, Stanfield RL, Lyumkis D, et al. (2013) Crystal structure of a soluble cleaved HIV-1 envelope trimer. Science 342: 1477–1483. doi: 10.1126/science.1245625 24179159
8. Lyumkis D, Julien JP, de Val N, Cupo A, Potter CS, et al. (2013) Cryo-EM structure of a fully glycosylated soluble cleaved HIV-1 envelope trimer. Science 342: 1484–1490. doi: 10.1126/science.1245627 24179160
9. Falkowska E, Le KM, Ramos A, Doores KJ, Lee JH, et al. (2014) Broadly neutralizing HIV antibodies define a glycan-dependent epitope on the prefusion conformation of gp41 on cleaved envelope trimers. Immunity 40: 657–668. doi: 10.1016/j.immuni.2014.04.009 24768347
10. Huang J, Kang BH, Pancera M, Lee JH, Tong T, et al. (2014) Broad and potent HIV-1 neutralization by a human antibody that binds the gp41-gp120 interface. Nature 515: 138–142. doi: 10.1038/nature13601 25186731
11. Scharf L, Scheid JF, Lee JH, West AP, Jr.Chen C, et al. (2014) Antibody 8ANC195 reveals a site of broad vulnerability on the HIV-1 envelope spike. Cell Rep 7: 785–795. doi: 10.1016/j.celrep.2014.04.001 24767986
12. Blattner C, Lee JH, Sliepen K, Derking R, Falkowska E, et al. (2014) Structural delineation of a quaternary, cleavage-dependent epitope at the gp41-gp120 interface on intact HIV-1 Env trimers. Immunity 40: 669–680. doi: 10.1016/j.immuni.2014.04.008 24768348
13. Walker LM, Phogat SK, Chan-Hui PY, Wagner D, Phung P, 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 19729618
14. Doores KJ, Burton DR, (2010) Variable loop glycan dependency of the broad and potent HIV-1-neutralizing antibodies PG9 and PG16. J Virol 84: 10510–10521. doi: 10.1128/JVI.00552-10 20686044
15. Burton DR, Pyati J, Koduri R, Sharp SJ, Thornton GB, et al. (1994) Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody. Science 266: 1024–1027. 7973652
16. Zhou T, Georgiev I, Wu X, Yang ZY, Dai K, 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 20616231
17. Wu X, Zhou T, Zhu J, Zhang B, Georgiev I, 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 21835983
18. Scheid JF, Mouquet H, Ueberheide B, Diskin R, Klein F, et al. (2011) Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding. Science 333: 1633–1637. doi: 10.1126/science.1207227 21764753
19. Liao HX, Lynch R, Zhou T, Gao F, Alam SM, et al. (2013) Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature 496: 469–476. doi: 10.1038/nature12053 23552890
20. Falkowska E, Ramos A, Feng Y, Zhou T, Moquin S, et al. (2012) PGV04, an HIV-1 gp120 CD4 binding site antibody, is broad and potent in neutralization but does not induce conformational changes characteristic of CD4. J Virol 86: 4394–4403. doi: 10.1128/JVI.06973-11 22345481
21. Balla-Jhagjhoorsingh SS, Corti D, Heyndrickx L, Willems E, Vereecken K, et al. (2013) The N276 glycosylation site is required for HIV-1 neutralization by the CD4 binding site specific HJ16 monoclonal antibody. PLoS One 8: e68863. doi: 10.1371/journal.pone.0068863 23874792
22. Sok D, Doores KJ, Briney B, Le KM, Saye-Francisco KL, et al. (2014) Promiscuous glycan site recognition by antibodies to the high-mannose patch of gp120 broadens neutralization of HIV. Sci Transl Med 6: 236ra263.
23. Pejchal R, Walker LM, Stanfield RL, Phogat SK, Koff WC, et al. (2010) Structure and function of broadly reactive antibody PG16 reveal an H3 subdomain that mediates potent neutralization of HIV-1. Proc Natl Acad Sci U S A 107: 11483–11488. doi: 10.1073/pnas.1004600107 20534513
24. Pancera M, McLellan JS, Wu X, Zhu J, Changela A, et al. (2010) 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 20538861
25. McLellan JS, Pancera M, Carrico C, Gorman J, Julien JP, et al. (2011) Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9. Nature 480: 336–343. doi: 10.1038/nature10696 22113616
26. Walker LM, Huber M, Doores KJ, Falkowska E, Pejchal R, et al. (2011) Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 477: 466–470. doi: 10.1038/nature10373 21849977
27. Bonsignori M, Hwang KK, Chen X, Tsao CY, Morris L, 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 21795340
28. Sok D, van Gils MJ, Pauthner M, Julien JP, Saye-Francisco KL, et al. (2014) Recombinant HIV envelope trimer selects for quaternary-dependent antibodies targeting the trimer apex. Proc Natl Acad Sci U S A 111: 17624–17629. doi: 10.1073/pnas.1415789111 25422458
29. Doria-Rose NA, Schramm CA, Gorman J, Moore PL, Bhiman JN, et al. (2014) Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies. Nature 509: 55–62. doi: 10.1038/nature13036 24590074
30. Pancera M, Shahzad-Ul-Hussan S, Doria-Rose NA, McLellan JS, Bailer RT, et al. (2013) Structural basis for diverse N-glycan recognition by HIV-1-neutralizing V1-V2-directed antibody PG16. Nat Struct Mol Biol 20: 804–813. doi: 10.1038/nsmb.2600 23708607
31. Julien JP, Lee JH, Cupo A, Murin CD, Derking R, et al. (2013) Asymmetric recognition of the HIV-1 trimer by broadly neutralizing antibody PG9. Proc Natl Acad Sci U S A 110: 4351–4356. doi: 10.1073/pnas.1217537110 23426631
32. Pejchal R, Doores KJ, Walker LM, Khayat R, Huang PS, 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 21998254
33. Kong L, Lee JH, Doores KJ, Murin CD, Julien JP, 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 23708606
34. Zwick MB, Labrijn AF, Wang M, Spenlehauer C, Saphire EO, et al. (2001) Broadly neutralizing antibodies targeted to the membrane-proximal external region of human immunodeficiency virus type 1 glycoprotein gp41. J Virol 75: 10892–10905. 11602729
35. Muster T, Steindl F, Purtscher M, Trkola A, Klima A, et al. (1993) A conserved neutralizing epitope on gp41 of human immunodeficiency virus type 1. J Virol 67: 6642–6647. 7692082
36. Huang J, Ofek G, Laub L, Louder MK, Doria-Rose NA, et al. (2012) Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature 491: 406–412. doi: 10.1038/nature11544 23151583
37. Ma BJ, Alam SM, Go EP, Lu X, Desaire H, 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 21909262
38. Kim AS, Leaman DP, Zwick MB, (2014) Antibody to gp41 MPER alters functional properties of HIV-1 Env without complete neutralization. PLoS Pathog 10: e1004271. doi: 10.1371/journal.ppat.1004271 25058619
39. Calarese DA, Scanlan CN, Zwick MB, Deechongkit S, Mimura Y, et al. (2003) Antibody domain exchange is an immunological solution to carbohydrate cluster recognition. Science 300: 2065–2071. 12829775
40. Sanders RW, Venturi M, Schiffner L, Kalyanaraman R, Katinger H, et al. (2002) The mannose-dependent epitope for neutralizing antibody 2G12 on human immunodeficiency virus type 1 glycoprotein gp120. J Virol 76: 7293–7305. 12072528
41. Scanlan CN, Pantophlet R, Wormald MR, Ollmann Saphire E, Stanfield R, et al. (2002) The broadly neutralizing anti-human immunodeficiency virus type 1 antibody 2G12 recognizes a cluster of alpha1—>2 mannose residues on the outer face of gp120. J Virol 76: 7306–7321. 12072529
42. Wang W, Nie J, Prochnow C, Truong C, Jia Z, et al. (2013) A systematic study of the N-glycosylation sites of HIV-1 envelope protein on infectivity and antibody-mediated neutralization. Retrovirology 10: 14. doi: 10.1186/1742-4690-10-14 23384254
43. Euler Z, Bunnik EM, Burger JA, Boeser-Nunnink BD, Grijsen ML, et al. (2011) Activity of broadly neutralizing antibodies, including PG9, PG16, and VRC01, against recently transmitted subtype B HIV-1 variants from early and late in the epidemic. J Virol 85: 7236–7245. doi: 10.1128/JVI.00196-11 21561918
44. Mouquet H, Scharf L, Euler Z, Liu Y, Eden C, et al. (2012) Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies. Proc Natl Acad Sci U S A 109: E3268–3277. doi: 10.1073/pnas.1217207109 23115339
45. Khayat R, Lee JH, Julien JP, Cupo A, Klasse PJ, et al. (2013) Structural characterization of cleaved, soluble HIV-1 envelope glycoprotein trimers. J Virol 87: 9865–9872. doi: 10.1128/JVI.01222-13 23824817
46. Pritchard LK, Spencer DI, Royle L, Vasiljevic S, Krumm SA, et al. (2015) Glycan microheterogeneity at the PGT135 antibody recognition site on HIV-1 gp120 reveals a molecular mechanism for neutralization resistance. J Virol.
47. Ketas TJ, Holuigue S, Matthews K, Moore JP, Klasse PJ, (2012) Env-glycoprotein heterogeneity as a source of apparent synergy and enhanced cooperativity in inhibition of HIV-1 infection by neutralizing antibodies and entry inhibitors. Virology 422: 22–36. doi: 10.1016/j.virol.2011.09.019 22018634
48. Poignard P, Moulard M, Golez E, Vivona V, Franti M, et al. (2003) Heterogeneity of envelope molecules expressed on primary human immunodeficiency virus type 1 particles as probed by the binding of neutralizing and nonneutralizing antibodies. J Virol 77: 353–365. 12477840
49. Burton DR, Hessell AJ, Keele BF, Klasse PJ, Ketas TA, et al. (2011) Limited or no protection by weakly or nonneutralizing antibodies against vaginal SHIV challenge of macaques compared with a strongly neutralizing antibody. Proc Natl Acad Sci U S A 108: 11181–11186. doi: 10.1073/pnas.1103012108 21690411
50. Mascola JR, Lewis MG, Stiegler G, Harris D, VanCott TC, et al. (1999) Protection of Macaques against pathogenic simian/human immunodeficiency virus 89.6PD by passive transfer of neutralizing antibodies. J Virol 73: 4009–4018. 10196297
51. Mascola JR, Stiegler G, VanCott TC, Katinger H, Carpenter CB, et al. (2000) Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies. Nat Med 6: 207–210. 10655111
52. Moldt B, Rakasz EG, Schultz N, Chan-Hui PY, Swiderek K, 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 U S A 109: 18921–18925. doi: 10.1073/pnas.1214785109 23100539
53. Shingai M, Donau OK, Plishka RJ, Buckler-White A, Mascola JR, et al. (2014) Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques. J Exp Med 211: 2061–2074. doi: 10.1084/jem.20132494 25155019
54. Watkins JD, Sholukh AM, Mukhtar MM, Siddappa NB, Lakhashe SK, et al. (2013) Anti-HIV IgA isotypes: differential virion capture and inhibition of transcytosis are linked to prevention of mucosal R5 SHIV transmission. AIDS 27: F13–20. doi: 10.1097/QAD.0b013e328360eac6 23775002
55. Watkins JD, Siddappa NB, Lakhashe SK, Humbert M, Sholukh A, et al. (2011) An anti-HIV-1 V3 loop antibody fully protects cross-clade and elicits T-cell immunity in macaques mucosally challenged with an R5 clade C SHIV. PLoS One 6: e18207. doi: 10.1371/journal.pone.0018207 21483815
56. Barouch DH, Whitney JB, Moldt B, Klein F, Oliveira TY, et al. (2013) Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature 503: 224–228. doi: 10.1038/nature12744 24172905
57. Halper-Stromberg A, Lu CL, Klein F, Horwitz JA, Bournazos S, et al. (2014) Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice. Cell 158: 989–999. doi: 10.1016/j.cell.2014.07.043 25131989
58. Horwitz JA, Halper-Stromberg A, Mouquet H, Gitlin AD, Tretiakova A, et al. (2013) HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice. Proc Natl Acad Sci U S A 110: 16538–16543. doi: 10.1073/pnas.1315295110 24043801
59. Klein F, Halper-Stromberg A, Horwitz JA, Gruell H, Scheid JF, et al. (2012) HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature 492: 118–122. doi: 10.1038/nature11604 23103874
60. Shingai M, Nishimura Y, Klein F, Mouquet H, Donau OK, et al. (2013) Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia. Nature 503: 277–280. doi: 10.1038/nature12746 24172896
61. Pegu A, Yang ZY, Boyington JC, Wu L, Ko SY, et al. (2014) Neutralizing antibodies to HIV-1 envelope protect more effectively in vivo than those to the CD4 receptor. Sci Transl Med 6: 243ra288.
62. Richman DD, Wrin T, Little SJ, Petropoulos CJ, (2003) Rapid evolution of the neutralizing antibody response to HIV type 1 infection. Proc Natl Acad Sci U S A 100: 4144–4149. 12644702
63. Li M, Gao F, Mascola JR, Stamatatos L, Polonis VR, et al. (2005) Human immunodeficiency virus type 1 env clones from acute and early subtype B infections for standardized assessments of vaccine-elicited neutralizing antibodies. J Virol 79: 10108–10125. 16051804
64. Mann AM, Rusert P, Berlinger L, Kuster H, Gunthard HF, et al. (2009) HIV sensitivity to neutralization is determined by target and virus producer cell properties. AIDS 23: 1659–1667. doi: 10.1097/QAD.0b013e32832e9408 19581791
65. Rusert P, Krarup A, Magnus C, Brandenberg OF, Weber J, et al. (2011) Interaction of the gp120 V1V2 loop with a neighboring gp120 unit shields the HIV envelope trimer against cross-neutralizing antibodies. J Exp Med 208: 1419–1433. doi: 10.1084/jem.20110196 21646396