Crystal structure of a neutralizing human IgG against HIV-1: A template for vaccine design

We present the crystal structure at 2.7 angstrom resolution of the human an tibody lgG1 b12. Antibody b12 recognizes the CD4-binding site of human immu nodeficiency virus-1 (HIV-1) gp120 and is one of only two known antibodies against gp120 capable of broad and potent neutralization of primary HIV-1 i solates. A key feature of the antibody-combining site is the protruding, fi nger-like long CDR H3 that can penetrate the recessed CD4-binding site of g p120. A docking model of b12 and gp120 reveals severe structural constraint s that explain the extraordinary challenge in eliciting effective neutraliz ing antibodies similar to b12. The structure, together with mutagenesis stu dies, provides a rationale for the extensive cross-reactivity of b12 and a valuable framework for the design of HIV-1 vaccines capable of eliciting b1 2-like activity.