Human Domain Antibodies to Conserved Sterically Restricted Regions on gp120 as Exceptionally Potent Cross-Reactive HIV-1 Neutralizers

摘要: The antibody access to some conserved structures on the HIV-1 envelope glycoprotein (Env) is sterically restricted. We have hypothesized that smallest independently folded fragments (domains) could exhibit exceptionally potent and broadly cross-reactive neutralizing activity by targeting hidden epitopes are not accessible larger antibodies. To test this hypothesis, we constructed a large (size 2.5 × 1010), highly diversified library of human variable domains (domain antibodies) used it for selection binders Env panning sequentially against Envs from different isolates. highest affinity binder, m36, neutralized all tested isolates clades A– D with an average higher than C34, peptide similar fusion inhibitor T20, which in clinical use, m9, exhibits superior known Large-size proteins m36 exhibited diminished but preincubation virions soluble CD4 restored it, suggesting epitope restricted induced (CD4i). M36 bound gp120-CD4 complexes better gp120 alone competed CD4i only reported representative promising class potent, inhibitors based domain It has potential prevention therapy as agent exploration closely guarded implications design small molecule elucidation mechanisms virus entry evasion immune responses.