Structure and immune recognition of trimeric pre-fusion HIV-1 Env

Nature

Volumn 514, Issue 7253, 2014, Pages 455-461

  Pancera, Marie ^a   Zhou, Tongqing ^a   Druz, Aliaksandr ^a   Georgiev, Ivelin S ^a   Soto, Cinque ^a   Gorman, Jason ^a   Huang, Jinghe ^a   Acharya, Priyamvada ^a   Chuang, Gwo Yu ^a   Ofek, Gilad ^a   Stewart Jones, Guillaume B E ^a   Stuckey, Jonathan ^a   Bailer, Robert T ^a   Joyce, M Gordon ^a   Louder, Mark K ^a   Tumba, Nancy ^b   Yang, Yongping ^a   Zhang, Baoshan ^a   Cohen, Myron S ^c   Haynes, Barton F ^d   Mascola, John R ^a   Morris, Lynn ^b,e,f   Munro, James B ^g   Blanchard, Scott C ^h   Mothes, Walther ^g   Connors, Mark ^a   Kwong, Peter D ^a   more..

^a NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES   (United States)

^b NATIONAL INSTITUTE FOR COMMUNICABLE DISEASES   (South Africa)

^c UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

^d DUKE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e UNIVERSITY OF THE WITWATERSRAND   (South Africa)

^f UNIVERSITY OF KWAZULU NATAL   (South Africa)

^g YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^h WEILL CORNELL MEDICAL COLLEGE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GLYCOPROTEIN GP 41; HUMAN IMMUNODEFICIENCY VIRUS ANTIGEN; NEUTRALIZING ANTIBODY; GLYCOPROTEIN GP 120; HUMAN IMMUNODEFICIENCY VIRUS ANTIBODY; HUMAN IMMUNODEFICIENCY VIRUS VACCINE; POLYSACCHARIDE; PROTEIN SUBUNIT;

AMINO ACID; ANTIBODY; ANTIGEN; HUMAN IMMUNODEFICIENCY VIRUS; IMMUNE RESPONSE; RECOGNITION;

AMINO TERMINAL SEQUENCE; ANTIGEN RECOGNITION; ARTICLE; CARBOXY TERMINAL SEQUENCE; HUMAN IMMUNODEFICIENCY VIRUS 1; IMMUNE EVASION; NONHUMAN; PRIORITY JOURNAL; PROTEIN CONFORMATION; VIRUS ENTRY; VIRUS ENVELOPE; VIRUS MORPHOLOGY; AMINO ACID SEQUENCE; CHEMICAL STRUCTURE; CHEMISTRY; COHORT ANALYSIS; GENETIC VARIABILITY; GENETICS; GLYCOSYLATION; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IMMUNOLOGY; MEMBRANE FUSION; MOLECULAR GENETICS; PROTEIN MULTIMERIZATION; PROTEIN QUATERNARY STRUCTURE; PROTEIN SUBUNIT; STRUCTURAL HOMOLOGY; X RAY CRYSTALLOGRAPHY;

HUMAN IMMUNODEFICIENCY VIRUS 1;

AIDS VACCINES; AMINO ACID SEQUENCE; ANTIBODIES, NEUTRALIZING; COHORT STUDIES; CRYSTALLOGRAPHY, X-RAY; GENETIC VARIATION; GLYCOSYLATION; HIV ANTIBODIES; HIV ENVELOPE PROTEIN GP120; HIV ENVELOPE PROTEIN GP41; HIV INFECTIONS; HUMANS; IMMUNE EVASION; MEMBRANE FUSION; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; POLYSACCHARIDES; PROTEIN MULTIMERIZATION; PROTEIN STRUCTURE, QUATERNARY; PROTEIN SUBUNITS; STRUCTURAL HOMOLOGY, PROTEIN; VIRUS INTERNALIZATION;

EID: 84909640954     PISSN: 00280836     EISSN: 14764687     Source Type: Journal    
DOI: 10.1038/nature13808     Document Type: Article

References (127)

1. The Joint United Nations Programme on HIV/AIDS. UNAIDS report on the global AIDS epidemic 2013 http://www.unaids.org/en/media/unaids/contentassets/ documents/epidemiology/2013/gr2013/unaids-global?report-2013-en.pdf (2013).
2. Wyatt, R. & Sodroski, J. The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens. Science 280, 1884-1888 (1998).
3. Wei, X. et al. Antibody neutralization and escape by HIV-1. Nature 422, 307-312 (2003).
4. Leonard, C. K. et al. 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 (1990).
5. Cimbro, R. et al. Tyrosine sulfation in the second variable loop (V2) of HIV-1 gp120 stabilizes V2-V3 interaction and modulates neutralization sensitivity. Proc. Natl Acad. Sci. USA 111, 3152-3157 (2014).
6. Li, Y. et al. Effects of inefficient cleavage of the signal sequence of HIV-1 gp 120 on its association with calnexin, folding, and intracellular transport. Proc. Natl Acad. Sci. USA 93, 9606-9611 (1996).
7. Kwong, P. D. et al. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 393, 648-659 (1998).
8. Chan, D. C., Fass, D., Berger, J. M. & Kim, P. S. Core structure of gp41 from the HIV envelope glycoprotein. Cell 89, 263-273 (1997).
9. Weissenhorn, W., Dessen, A., Harrison, S. C., Skehel, J. J. & Wiley, D. C. Atomic structure of the ectodomain from HIV-1 gp41. Nature 387, 426-430 (1997).
10. Julien, J. P. et al. Crystal structure of a soluble cleaved HIV-1 envelope trimer. Science 342, 1477-1483 (2013).
11. Lyumkis, D. et al. Cryo-EM structure of a fully glycosylated soluble cleaved HIV-1 envelope trimer. Science 342, 1484-1490 (2013).
12. Walker, L. M. et al. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 477, 466-470 (2011).
13. Huang, J. et al. Broad and potent neutralization of HIV-1 by a human antibody that recognizes an intersubunit site on the envelope glycoprotein. Nature http:// dx.doi.org/10.1038/nature13601 (3 September 2014).
14. Sanders, R. W. et al. Stabilization of the soluble, cleaved, trimeric form of the envelope glycoprotein complex of human immunodeficiency virus type 1. J. Virol. 76, 8875-8889 (2002).
15. Julien, J. P. et al. Asymmetric recognition of the HIV-1 trimer by broadly neutralizing antibody PG9. Proc. Natl Acad. Sci. USA 110, 4351-4356 (2013).
16. Sanders, R. W. et al. A next-generation cleaved, soluble HIV-1 Env trimer, BG505 SOSIP.664 gp140, expresses multiple epitopes for broadly neutralizing but not non-neutralizing antibodies. PLoS Pathog. 9, e1003618 (2013).
17. Ringe, R. P. et al. Cleavage strongly influences whether soluble HIV-1 envelope glycoprotein trimers adopt a native-like conformation. Proc. Natl Acad. Sci. USA 110, 18256-18261 (2013).
18. Munro, J. B. et al. Conformational dynamics of single HIV-1 envelope trimers on the surface of native virions. Science http://dx.doi.org/10.1126/ science.1254426 (2014).
19. Julien, J. P. et al. 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 (2013).
20. Georgiev, I. S. et al. Delineating antibody recognition in polyclonal sera from patterns of HIV-1 isolate neutralization. Science 340, 751-756 (2013).
21. Mao, Y. et al. Subunit organization of the membrane-bound HIV-1 envelope glycoprotein trimer. Nature Struct. Mol. Biol. 19, 893-899 (2012).
22. Pancera, M. et al. Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobility. Proc. Natl Acad. Sci. USA 107, 1166-1171 (2010).
23. Finzi, A. et al. Topological layers in the HIV-1 gp120 inner domain regulate gp41 interaction and CD4-triggered conformational transitions. Mol. Cell 37, 656-667 (2010).
24. Buzon, V. et al. Crystal structure of HIV-1 gp41 including both fusion peptide and membrane proximal external regions. PLoS Pathog. 6, e1000880 (2010).
25. Caffrey, M. et al. Three-dimensional solution structure of the 44kDa ectodomain of SIV gp41. EMBO J. 17, 4572-4584 (1998).
26. Nishikawa, K., Ooi, T., Saito, N. & Isogai, Y. Tertiary structure of proteins. 1. Representation and computation of conformations. J. Phys. Soc. Jpn. 32, 1331-1337 (1972).
27. Bartesaghi, A., Merk, A., Borgnia, M. J., Milne, J. L. & Subramaniam, S. Prefusion structure of trimeric HIV-1 envelope glycoprotein determined by cryo-electron microscopy. Nature Struct. Mol. Biol. 20, 1352-1357 (2013).
28. Liu, J., Bartesaghi, A., Borgnia, M. J., Sapiro, G. & Subramaniam, S. Molecular architecture of native HIV-1 gp120 trimers. Nature 455, 109-113 (2008).
29. White, T. A. et al. Molecular architectures of trimeric SIV and HIV-1 envelope glycoproteins on intact viruses: strain-dependent variation in quaternary structure. PLoS Pathog. 6, e1001249 (2010).
30. Huang, C. C. et al. Structure of a V3-containing HIV-1 gp120 core. Science 310, 1025-1028 (2005).
31. McLellan, J. S. et al. Structure of RSV fusion glycoprotein trimer bound to a prefusion-specific neutralizing antibody. Science 340, 1113-1117 (2013).
32. Yuan, W., Craig, S., Si, Z., Farzan, M. & Sodroski, J. CD4-induced T-20 binding to human immunodeficiency virus type 1 gp120 blocks interaction with the CXCR4 coreceptor. J. Virol. 78, 5448-5457 (2004).
33. Huang, C. C. et al. Structures of the CCR5 N terminus and of a tyrosine-sulfated antibody with HIV-1 gp120 and CD4. Science 317, 1930-1934 (2007).
34. Moore, J. P., McKeating, J. A., Weiss, R. A. & Sattentau, Q. J. Dissociation of gp120 from HIV-1 virions induced by soluble CD4. Science 250, 1139-1142 (1990).
35. Wilson, I. A., Skehel, J. J. & Wiley, D. C. Structure of the haemagglutininmembrane glycoprotein of influenza virus at 3A resolution. Nature 289, 366-373 (1981).
36. Bullough, P. A., Hughson, F. M., Skehel, J. J. & Wiley, D. C. Structure of influenza haemagglutinin at the pH of membrane fusion. Nature 371, 37-43 (1994).
37. McLellan, J. S., Yang, Y., Graham, B. S. & Kwong, P. D. Structure of respiratory syncytial virus fusion glycoprotein in the postfusion conformation reveals preservation of neutralizing epitopes. J. Virol. 85, 7788-7796 (2011).
38. Weissenhorn, W., Carfi, A., Lee, K. H., Skehel, J. J. & Wiley, D. C. Crystal structure of the Ebola virus membrane fusion subunit, GP2, from the envelope glycoprotein ectodomain. Mol. Cell 2, 605-616 (1998).
39. Lee, J. E. et al. Structure of the Ebola virus glycoprotein bound to an antibody from a human survivor. Nature 454, 177-182 (2008).
40. Colman, P. M. & Lawrence, M. C. The structural biology of type I viral membrane fusion. Nature Rev. Mol. Cell Biol. 4, 309-319 (2003).
41. Wyatt, R. et al. The antigenic structure of the HIV gp120 envelope glycoprotein. Nature 393, 705-711 (1998).
42. Hraber, P. et al. Prevalence of broadly neutralizing antibody responses during chronic HIV-1 infection. AIDS 28, 163-169 (2014).
43. Yang, X., Kurteva, S., Ren, X., Lee, S. & Sodroski, J. Stoichiometry of envelope glycoprotein trimers in the entry of humanimmunodeficiency virus type 1. J. Virol. 79, 12132-12147 (2005).
44. Kwong, P. D. et al. HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. Nature 420, 678-682 (2002).
45. Klein, J. S. & Bjorkman, P. J. Few and far between: how HIV may be evading antibody avidity. PLoS Pathog. 6, e1000908 (2010).
46. Wu, X. et al.Neutralization escape variants of humanimmunodeficiency virus type 1 are transmitted from mother to infant. J. Virol. 80, 835-844 (2006).
47. McLellan, J. S. et al. Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science 342, 592-598 (2013).
48. Kanekiyo, M. et al. Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies. Nature 499, 102-106 (2013).
49. Liao, H.-X. et al. Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature 496, 469-476 (2013).
50. Doria-Rose, N. A. et al. Developmental pathway for potent V1V2-directed HIVneutralizing antibodies. Nature 509, 55-62 (2014).
51. McLellan, J. S. et al. Structure of HIV-1 gp120 V1/V2 domain with broadly neutralizing antibody PG9. Nature 480, 336-343 (2011).
52. Majeed, S. et al. Enhancing protein crystallization through precipitant synergy. Structure 11, 1061-1070 (2003).
53. Kwong, P. D. & Liu, Y. Use of cryoprotectants in combination with immiscible oils for flash cooling macromolecular crystals. J. Appl. Cryst. 32, 102-105 (1999).
54. Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307-326 (1997).
55. Adams, P. D. et al. Recent developments in the PHENIX software for automated crystallographic structure determination. J. Synchrotron Radiat. 11, 53-55 (2004).
56. Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D 60, 2126-2132 (2004).
57. Davis, I. W., Murray, L. W., Richardson, J. S. & Richardson, D. C. MOLPROBITY: structure validation and all-atom contact analysis for nucleic acids and their complexes. Nucleic Acids Res. 32, W615-W619 (2004).
58. Lin, C. W. & Ting, A. Y. Transglutaminase-catalyzed site-specific conjugation of small-molecule probes to proteins in vitro and on the surface of living cells. J. Am. Chem. Soc. 128, 4542-4543 (2006).
59. Zhou, Z. et al. Genetically encoded short peptide tags for orthogonal protein labeling by Sfp and AcpS phosphopantetheinyl transferases. ACS Chem. Biol. 2, 337-346 (2007).
60. Dave, R., Terry, D. S., Munro, J. B. & Blanchard, S. C. Mitigating unwanted photophysical processes for improved single-molecule fluorescence imaging. Biophys. J. 96, 2371-2381 (2009).
61. Aitken, C. E., Marshall, R. A. & Puglisi, J. D. An oxygen scavenging system for improvement of dye stability in single-molecule fluorescence experiments. Biophys. J. 94, 1826-1835 (2008).
62. Richards, F. M. & Kundrot, C. E. Identification of structural motifs from protein coordinate data: secondary structure and first-level supersecondary structure. Proteins 3, 71-84 (1988).
63. Xiang, Z., Soto, C. S. & Honig, B. Evaluating conformational free energies: the colony energy and its application to the problem of loop prediction. Proc. Natl Acad. Sci. USA 99, 7432-7437 (2002).
64. Xiang, Z. & Honig, B. Extending the accuracy limits of prediction for side-chain conformations. J. Mol. Biol. 311, 421-430 (2001).
65. Kirschner, K. N. et al. GLYCAM06: a generalizable biomolecular force field. Carbohydrates. J. Comput. Chem. 29, 622-655 (2008).
66. Cornell, W. D. et al. A second generation force field for the simulation of proteins, nucleic acids, and organic molecules. J. Am. Chem. Soc. 117, 5179-5197 (1995).
67. Tomaras, G. D. et al. Initial B-cell responses to transmitted human immunodeficiency virus type 1: virion-binding immunoglobulin M (IgM) and IgG antibodies followed by plasma anti-gp41 antibodies with ineffective control of initial viremia. J. Virol. 82, 12449-12463 (2008).
68. Tomaras, G. D. et al. Polyclonal B cell responses to conserved neutralization epitopes in a subset of HIV-1-infected individuals. J. Virol. 85, 11502-11519 (2011).
69. Li, M. et al.Humanimmunodeficiency virus type1 env clones fromacute and early subtype b infections for standardized assessments of vaccine-elicited neutralizing antibodies. J. Virol. 79, 10108-10125 (2005).
70. Zhou, T. et al. Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science 329, 811-817 (2010).
71. Zhou, T. et al. Structural definition of a conserved neutralization epitope on HIV-1 gp120. Nature 445, 732-737 (2007).
72. Scharf, L. et al. Antibody 8ANC195 reveals a site of broad vulnerability on the HIV- 1 envelope spike. Cell Rep. 7, 785-795 (2014).
73. Calarese, D. A. et al. Antibody domain exchange is an immunological solution to carbohydrate cluster recognition. Science 300, 2065-2071 (2003).
74. Xu, R. et al. Structural basis of preexisting immunity to the 2009 H1N1 pandemic influenza virus. Science 328, 357-360 (2010).
75. Ekiert, D. C. et al. Cross-neutralization of influenza A viruses mediated by a single antibody loop. Nature 489, 526-532 (2012).
76. Sui, J. et al. Structural and functional bases for broad-spectrum neutralization of avianand human influenzaAviruses.Nature Struct.Mol. Biol.16,265-273(2009).
77. Friesen, R. H. et al. A common solution to group 2 influenza virus neutralization. Proc. Natl Acad. Sci. USA 111, 445-450 (2014).
78. McLellan, J. S. et al. Structural basis of respiratory syncytial virus neutralization by motavizumab. Nature Struct. Mol. Biol. 17, 248-250 (2010).
79. McLellan, J. S. et al. Structure of a major antigenic site on the respiratory syncytial virus fusion glycoprotein in complex with neutralizing antibody 101F. J. Virol. 84, 12236-12244 (2010).
80. Mann, H. B. W. & Donald, R. On a test of whether one of two random variables is stochastically larger than the other. Ann. Math. Stat. 18, 50-60 (1947).
81. The PyMOL Molecular Graphics System. (DeLano Scientific, San Carlos, California, 2002).
82. Weis, W. I., Brunger, A. T., Skehel, J. J. & Wiley, D. C. Refinement of the influenza virus hemagglutinin by simulated annealing. J. Mol. Biol. 212, 737-761 (1990).
83. Chen, J., Skehel, J. J. & Wiley, D. C. N- and C-terminal residues combine in the fusion-pH influenza hemagglutinin HA(2) subunit to form an N cap that terminates the triple-stranded coiled coil. Proc. Natl Acad. Sci. USA 96, 8967-8972 (1999).
84. Malashkevich, V. N. et al. Core structure of the envelope glycoprotein GP2 from Ebola virus at 1.9-A resolution. Proc. Natl Acad. Sci. USA 96, 2662-2667 (1999).
85. Lin, Y. P. et al. Evolution of the receptor binding properties of the influenza A(H3N2) hemagglutinin. Proc. Natl Acad. Sci. USA 109, 21474-21479 (2012).
86. Chen, L. et al. Structural basis ofimmune evasion at the site ofCD4 attachment on HIV-1 gp120. Science 326, 1123-1127 (2009).
87. Rini, J. M. et al. Crystal structure of a human immunodeficiency virus type 1 neutralizing antibody, 50.1, in complex with its V3 loop peptide antigen. Proc. Natl Acad. Sci. USA 90, 6325-6329 (1993).
88. Stanfield, R. et al. Dual conformations for the HIV-1 gp120 V3 loop in complexes with different neutralizing fabs. Structure 7, 131-142 (1999).
89. Tugarinov, V., Zvi, A., Levy, R. & Anglister, J. A cis proline turn linking two b-hairpin strands in the solutionstructure of anantibody-bound HIV-1IIIBV3peptide.Nature Struct. Biol. 6, 331-335 (1999).
90. Ofek, G. et al. Structure and mechanistic analysis of the anti-human immunodeficiency virus type 1 antibody 2F5 in complex with its gp41 epitope. J. Virol. 78, 10724-10737 (2004).
91. Cardoso, R. M. et al. Broadly neutralizing anti-HIV antibody 4E10 recognizes a helical conformation of a highly conserved fusion-associated motif in gp41. Immunity 22, 163-173 (2005).
92. Luftig, M. A. et al. Structural basis for HIV-1 neutralization by a gp41 fusion intermediate-directed antibody. Nature Struct. Mol. Biol. 13, 740-747 (2006).
93. Cardoso, R. M. et al. Structural basis of enhanced binding of extendedandhelically constrained peptide epitopes of the broadly neutralizing HIV-1 antibody 4E10. J. Mol. Biol. 365, 1533-1544 (2007).
94. Grigoryan, G. & Keating, A. E. Structural specificity in coiled-coil interactions. Curr. Opin. Struct. Biol. 18, 477-483 (2008).
95. Helseth, E., Olshevsky, U., Furman, C. & Sodroski, J. Human immunodeficiency virus type 1 gp120 envelope glycoprotein regions important for association with the gp41 transmembrane glycoprotein. J. Virol. 65, 2119-2123 (1991).
96. Thali, M., Furman, C., Helseth, E., Repke, H. & Sodroski, J. Lack of correlation between soluble CD4-induced shedding of the human immunodeficiency virus type 1 exterior envelope glycoprotein and subsequent membrane fusion events. J. Virol. 66, 5516-5524 (1992).
97. Cao, J. et al. Effects of amino acid changes in the extracellular domain of the human immunodeficiency virus type 1 gp41 envelope glycoprotein. J. Virol. 67, 2747-2755 (1993).
98. Leavitt, M., Park, E. J., Sidorov, I. A., Dimitrov, D. S. & Quinnan, G. V. Jr. Concordant modulation of neutralization resistance and high infectivity of the primary human immunodeficiency virus type 1 MN strain and definition of a potential gp41 binding site in gp120. J. Virol. 77, 560-570 (2003).
99. Yang, X., Mahony, E., Holm, G. H., Kassa, A. & Sodroski, J. Role of the gp120 inner domain beta-sandwich in the interaction between the human immunodeficiency virus envelope glycoprotein subunits. Virology 313, 117-125 (2003).
100. Sen, J., Jacobs, A. & Caffrey, M. Role of the HIV gp120 conserved domain 5 in processing and viral entry. Biochemistry 47, 7788-7795 (2008).
101. Wang, J., Sen, J., Rong, L. & Caffrey, M. Role of the HIV gp120 conserved domain 1 in processing and viral entry. J. Biol. Chem. 283, 32644-32649 (2008).
102. Lawless, M. K. et al. HIV-1 membrane fusion mechanism: structural studies of the interactions between biologically-active peptides from gp41. Biochemistry 35, 13697-13708 (1996).
103. Chen, C. H., Matthews, T. J., McDanal, C. B., Bolognesi, D. P. & Greenberg, M. L. A molecular clasp in the human immunodeficiency virus (HIV) type 1 TM protein determines the anti-HIV activity of gp41 derivatives: implication for viral fusion. J. Virol. 69, 3771-3777 (1995).
104. Root, M. J., Kay, M. S. & Kim, P. S. Protein design of an HIV-1 entry inhibitor. Science 291, 884-888 (2001).
105. Gustchina, E. et al. Structural basis of HIV-1 neutralization by affinity matured Fabs directed against the internal trimeric coiled-coil of gp41. PLoS Pathog. 6, e1001182 (2010).
106. Sabin, C. et al. Crystal structure and size-dependent neutralization properties of HK20, a human monoclonal antibody binding to the highly conserved heptad repeat 1 of gp41. PLoS Pathog. 6, e1001195 (2010).
107. Blattner, C. et al. Structural delineation of a quaternary, cleavage-dependent epitope at the gp41-gp120 interface on intact HIV-1 Env trimers. Immunity 40, 669-680 (2014).
108. Yasmeen, A. et al. Differential binding of neutralizing and non-neutralizing antibodies to native-like soluble HIV-1 Env trimers, uncleaved Env proteins, and monomeric subunits. Retrovirology 11, 41 (2014).
109. Falkowska, E. et al. Broadly neutralizing HIV antibodies define a glycan-dependent epitope on the prefusion conformation of gp41 on cleaved envelope trimers. Immunity 40, 657-668 (2014).
110. Thali, M. et al. Characterization of conserved humanimmunodeficiency virus type 1 gp120 neutralization epitopes exposed upon gp120-CD4 binding. J. Virol. 67, 3978-3988 (1993).
111. Guttman, M. et al. CD4-induced activation in a soluble HIV-1 Env trimer. Structure 22, 974-984 (2014).
112. Scheid, J. F. et al. Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding. Science 333, 1633-1637 (2011).
113. Walker, L. M. et al. Broad and potent neutralizing antibodies froman African donor reveal a new HIV-1 vaccine target. Science 326, 285-289 (2009).
114. Stanfield, R. L. & Wilson, I. A. Structural studies of human HIV-1 V3 antibodies. Hum. Antibodies 14, 73-80 (2005).
115. Rizzuto, C. D. et al. A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding. Science 280, 1949-1953 (1998).
116. Guan, Y. et al. Diverse specificity and effector functionamong human antibodies to HIV-1 envelope glycoprotein epitopes exposed by CD4 binding. Proc. Natl Acad. Sci. USA 110, E69-E78 (2013).
117. Gorny, M. K., VanCott, T. C., Williams, C., Revesz, K. & Zolla-Pazner, S. Effects of oligomerization on the epitopes of the human immunodeficiency virus type 1 envelope glycoproteins. Virology 267, 220-228 (2000).
118. Yuan, W. et al. Oligomer-specific conformations of the human immunodeficiency virus (HIV-1) gp41 envelope glycoprotein ectodomain recognized by human monoclonal antibodies. AIDS Res. Hum. Retroviruses 25, 319-328 (2009).
119. Moore, P. L. et al. Nature of nonfunctional envelope proteins on the surface of human immunodeficiency virus type 1. J. Virol. 80, 2515-2528 (2006).
120. Frey, G. et al. Distinct conformational states of HIV-1 gp41 are recognized by neutralizing and non-neutralizing antibodies. Nature Struct. Mol. Biol. 17, 1486-1491 (2010).
121. Miller, M. D. et al. A humanmonoclonal antibody neutralizes diverse HIV-1 isolates by binding a critical gp41 epitope. Proc. Natl Acad. Sci. USA 102, 14759-14764 (2005).
122. Chen, J. et al. Mechanism of HIV-1 neutralization by antibodies targeting a membrane-proximal region of gp41. J. Virol. 88, 1249-1258 (2014).
123. Frey, G. et al. A fusion-intermediate state of HIV-1 gp41 targeted by broadly neutralizing antibodies. Proc. Natl Acad. Sci. USA 105, 3739-3744 (2008).
124. Nicely, N. I. et al. Crystal structure of a non-neutralizing antibody to the HIV-1 gp41 membrane-proximal external region. Nature Struct. Mol. Biol. 17, 1492-1494 (2010).
125. Huang, J. et al. Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature 491, 406-412 (2012).
126. Chakrabarti, B. K. et al. HIV type 1 Env precursor cleavage state affects recognition by both neutralizing and nonneutralizing gp41 antibodies. AIDS Res. Hum. Retroviruses 27, 877-887 (2011).
127. Ruprecht, C. R. et al. MPER-specific antibodies induce gp120 shedding and irreversibly neutralize HIV-1. J. Exp. Med. 208, 439-454 (2011).