Structural Basis for HIV-1 gp120 Recognition by a Germ-line Version of a Broadly Neutralizing Antibody

Abstract

Following infection by HIV-1, the host immune response is unable to clear the virus due to a variety of factors, including rapid viral mutation and the establishment of latent reservoirs. The only target of neutralizing antibodies is the trimeric envelope (Env) spike complex, but HIV-1 can usually evade anti-spike antibodies due to rapid mutation of its two spike glycoproteins, gp120 and gp41, and structural features that allow the spike to hide conserved epitopes. Efforts to design an effective antibody-based vaccine against HIV-1 would benefit from understanding how germ-line B-cell receptors recognize the gp120/ gp41 envelope spike. Recently isolated from several infected individuals, potent VRC01-like (PVL) HIV-1 antibodies derived from the VH1–2*02 germ-line allele target the CD4 binding site on gp120. These antibodies have unprecedented potency and breadth for HIV-1 neutralization and some protect against HIV-1 infection in animal models. Since the VH1–2*02 germ-line allele is present in up to 95% of the population, it may be possible to elicit by vaccination similar CD4 binding site antibodies in other individuals. VH1–2*02 germ-line B-cell receptor interactions with gp120 were uncharacterized, which was a bottleneck for designing immunogens to elicit PVL antibodies.

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