Abstract
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.Supplementary informationThe online version of this article (doi:10.1038/nature05580) contains supplementary material, which is available to authorized users.
Highlights
The remarkable diversity, glycosylation and conformational flexibility of the human immunodeficiency virus type 1 (HIV-1) envelope (Env), including substantial rearrangement of the gp[120] glycoprotein upon binding the CD4 receptor, allow it to evade antibody-mediated neutralization
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]. This 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[3,4,5]
The gp[120] glycoprotein must bind to cell-surface CD4, alter its conformation to reveal a site for co-receptor attachment[15], and trigger conformational rearrangements in the gp[41] glycoprotein to mediate fusion of viral and host cell membranes[16,17]
Summary
The remarkable diversity, glycosylation and conformational flexibility of the human immunodeficiency virus type 1 (HIV-1) envelope (Env), including substantial rearrangement of the gp[120] glycoprotein upon binding the CD4 receptor, allow it to evade antibody-mediated neutralization. We determined the crystal structure of the broadly neutralizing antibody b12 in complex with one of the stabilized gp[120] molecules. Analysis of this structure, combined with detailed antigenic analyses of gp[120] molecules stabilized to various extents in the CD4-bound conformation, reveals the functionally conserved surface that allows for initial CD4 attachment, and provides an atomic-level description of the b12 epitope, which serves as a key target for humoral neutralization of HIV-1.
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