Mechanism of Neutralization by the Broadly Neutralizing HIV-1 Monoclonal Antibody VRC01

摘要: The structure of VRC01 in complex with the HIV-1 gp120 core reveals that this broadly neutralizing CD4 binding site (CD4bs) antibody partially mimics interaction primary virus receptor, CD4, gp120. Here, we extended investigation VRC01-gp120 to biologically relevant viral spike better understand mechanism VRC01-mediated neutralization and define elements associated resistance. In contrast or CD4bs monoclonal (MAb) b12 envelope glycoprotein (Env), occlusion epitope by quaternary constraints was not a major factor limiting neutralization. Mutagenesis studies indicated contacts within loop D, loop, V5 region were necessary for optimal neutralization, as suggested crystal structure. interactions soluble monomer, native did occur CD4-like manner; induce shedding from Env enhance gp41 membrane proximal external (MPER)-directed spike. Finally, display significant reactivity human antigens, boding well potential vivo applications. data indicate interacts context functional manner distinct CD4. It achieves potent precisely targeting without requiring alterations configuration avoiding steric imposed