Characterization of conserved human immunodeficiency virus type 1 gp120 neutralization epitopes exposed upon gp120-CD4 binding

Thali, Markus; Moore, John P.; Furman, Craig; Charles, Marie‐Hélène; Ho, David D.; Robinson, James E.; Sodroski, Joseph

doi:10.1128/jvi.67.7.3978-3988.1993

Cited by 602 publications

(312 citation statements)

References 86 publications

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“…Because the epitope for CD4-induced antibodies is only formed in the CD4-bound state 10,19,20 , we could use the increase in antibody onrate to assess the degree to which stabilization 'preformed' the variant gp120 molecules in the CD4-bound state. Reasonable correlations were observed between the on-rate for CD4-induced antibodies and the entropy of CD4 binding (r 5 0.74, P , 0.036 for antibody 17b (ref.…”

Section: Recognition Of the Cd4-binding Sitementioning

confidence: 99%

Structural definition of a conserved neutralization epitope on HIV-1 gp120

Zhou

Dey

et al. 2007

Nature

715

937

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The remarkable diversity, glycosylation and conformational flexibility of the human immunodeficiency virus type 1 (HIV-1) envelope (Env), including substantial rearrangement of the gp120 glycoprotein upon binding the CD4 receptor, allow it to evade antibody-mediated neutralization. Despite this complexity, the HIV-1 Env must retain conserved determinants that mediate CD4 binding. To evaluate how these determinants might provide opportunities for antibody recognition, we created variants of gp120 stabilized in the CD4-bound state, assessed binding of CD4 and of receptor-binding-site antibodies, and determined the structure at 2.3 Å resolution of the broadly neutralizing antibody b12 in complex with gp120. b12 binds to a conformationally invariant surface that overlaps a distinct subset of the CD4-binding site. This surface is involved in the metastable attachment of CD4, before the gp120 rearrangement required for stable engagement. A site of vulnerability, related to a functional requirement for efficient association with CD4, can therefore be targeted by antibody to neutralize HIV-1.The human immunodeficiency virus type 1 (HIV-1) crossed from chimpanzees to humans early in the twentieth century and has since infected ~1% of the world's adult population 1,2 . ThisCorrespondence and requests for materials should be addressed to P.D.K. (pdkwong@nih.gov). Author Contributions T.Z. and P.D.K. carried out structure-based stabilization, SPR analyses and structural determinations; L.X. and G.J.N. constructed gp120 substitutions and developed and implemented a high-throughput gp120-production system suitable for crystallization; B.D. and R.W. carried out ITC characterizations; A.J.H., M.B.Z. and D.R.B. provided b12, b3, b6, b11 and b13, and mutant b12 binding; D.V.R. and J.A. provided D1D2-Igαtp and associated SPR analyses; S.-H.X., X.Y. and J.S. provided OD1 and preliminary design and antigenic analyses; and M.-Y.Z. and D.S.D. provided m6, m14 and m18. All authors contributed to the manuscript preparation.Author Information Coordinates and structure factors have been deposited in the Protein Data Bank and may be obtained from the authors (accession codes 2nxy-2ny6 for the nine variant gp120 molecules with CD4 and 17b; accession code 2ny7 for the b12-gp120 complex). Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests. spread and the absence of an effective vaccine are to a large degree a consequence of the ability of HIV-1 to evade antibody-mediated neutralization 3-5 . On HIV-1, the only viral target available for neutralizing antibodies is the envelope spike, which is composed of three copies of the gp120 exterior envelope glycoprotein and three gp41 transmembrane glyco-protein molecules 6,7 . Genetic, immunological and structural studies of the HIV-1 envelope glycoproteins have revealed extraordinary diversity, manifest in a variety of immunodominant loops, as well as multiple overlapping mechanisms of humoral evasion, including se...

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Section: Recognition Of the Cd4-binding Sitementioning

confidence: 99%

Structural definition of a conserved neutralization epitope on HIV-1 gp120

Zhou

Dey

et al. 2007

Nature

715

937

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“…The Ig gene usage was also analyzed for 44 human mAbs specific for epitopes in the envelope proteins of HIV-1 other than V3; these included 11 anti-CD4bd mAbs, 12 anti-CD4i mAbs and 21 anti-gp41 mAbs (Table 3). Thirty-four nucleotide sequences for the Ig variable fragment of the heavy chain were obtained from published data or GenBank (Andris et al, 1991;Bagley et al, 1994;Barbas et al, 1993;Cavacini et al, 1998;David et al, 1995b;de Haard et al, 1998;Felgenhauer et al, 1990;Huang et al, 2004;Kunert et al, 1998;Kunert et al, 2004;Marasco et al, 1992;Moran et al, 1993;Thali et al, 1993;van der Donk et al, 1994;Zhang et al, 2004;Zwick et al, 2001) while 10 human anti-gp41 mAbs, 50-69 (Gorny et al, 1989), 126-6, 167-7, 181-D, 240-D and 246-D (Xu et al, 1991), 1281, 1342, 1367and 1379(Gorny et al, 2000, were produced and sequenced in our laboratory (Table 3).…”

Section: Human Anti-gp120 and Gp41 Mabsmentioning

confidence: 99%

Preferential use of the VH5-51 gene segment by the human immune response to code for antibodies against the V3 domain of HIV-1

Gorny

Wang

Williams

et al. 2009

Molecular Immunology

107

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Human anti-V3 monoclonal antibodies (mAbs) generated from HIV-1 infected individuals display diversity in the range of their cross-neutralization that may be related to their immunogenetic background. The study of the immunoglobulin (Ig) variable region gene usage of heavy chains have shown a preferential usage of the VH5-51 gene segment which was detected in 35% of 51 human anti-V3 mAbs. In contrast, human mAbs against other envelope regions of HIV-1 (anti-Env), including the CD4-binding domain, the CD4-induced epitope, and gp41 preferentially used the VH1-69 gene segment, and none of them used the VH5-51 gene. Furthermore, the usage of the VH4 family by anti-V3 mAbs was restricted to only one gene segment, VH4-59, while the VH3 gene family was used at a significantly lower frequency by all of the analyzed anti-HIV-1 mAbs. Multivariate analysis showed that usage of VH gene segments was significantly different between anti-V3 and anti-Env mAbs, and compared to antibodies from healthy subjects. In addition, the anti-V3 mAbs preferentially used the JH3 and D2-15 gene segments. The preferential usage of selected Ig gene segments and the characteristic pattern of Ig gene usage by anti-V3 mAbs can be related to the conserved structure of the V3 region.

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“…For example, because HIV gp120's binding site for its secondary cellular receptor (a chemokine receptor) is conserved, this surface provides an epitope that can be recognized by broadly neutralizing antibodies [26]. However, this conserved epitope assembles from dispersed structural elements only after gp120 has bound its primary receptor (CD4) [27,28].…”

Section: Engineering Stable Antigen Conformationsmentioning

confidence: 99%

Structure-based antigen design: a strategy for next generation vaccines

Dormitzer

Ulmer

Rappuoli³

2008

Trends in Biotechnology

153

113

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Vaccine design is progressing from empiricism towards the increasingly rational presentation of the targets of protective immunity. Nevertheless, most current vaccine antigens are essentially the native macromolecules of pathogens. These molecules are adapted to evade, not induce, immunity. High resolution structures reveal the electrostatic surfaces recognized by neutralizing antibodies and the architectures underlying these surfaces, thereby identifying which substructures must be left intact and which can be changed to optimize biochemical and immunologic performance. Armed with detailed structural information, we can engineer optimized antigens that are more stable, homogeneous, and efficiently produced, making immunization more practical and affordable. Understanding the structural basis for immunogenicity and immunodominance will allow us to improve vaccine efficacy and broaden the range of vaccine-preventable diseases.

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Characterization of conserved human immunodeficiency virus type 1 gp120 neutralization epitopes exposed upon gp120-CD4 binding

Cited by 602 publications

References 86 publications

Structural definition of a conserved neutralization epitope on HIV-1 gp120

Structural definition of a conserved neutralization epitope on HIV-1 gp120

Preferential use of the VH5-51 gene segment by the human immune response to code for antibodies against the V3 domain of HIV-1

Structure-based antigen design: a strategy for next generation vaccines

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