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

Zhou, Tongqing; Xu, Ling; Dey, Barna; Hessell, Ann J.; Van Ryk, Donald; Xiang, Shi-Hua; Yang, Xinzhen; Zhang, Mei-Yun; Zwick, Michael B.; Arthos, James; Burton, Dennis R.; Dimitrov, Dimiter S.; Sodroski, Joseph; Wyatt, Richard; Nabel, Gary J.; Kwong, Peter D.

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 Ã… 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.