Identification of variant HIV envelope proteins with enhanced affinities for precursors to anti-gp41 broadly neutralizing antibodies.

摘要: HIV envelope protein (Env) is the sole target of broadly neutralizing antibodies (BNAbs) that are capable diverse strains HIV. While BNAbs develop spontaneously in a subset HIV-infected patients, efforts to design an protein-based immunogen elicit antibody responses have so far been unsuccessful. It hypothesized primary barrier eliciting fact proteins bind poorly germline-encoded unmutated common ancestor (UCA) precursors BNAbs. To identify variant forms Env with increased affinities for UCA 4E10 and 10E8, which Membrane Proximal External Region (MPER) Env, libraries randomly mutated variants were expressed yeast surface display system screened using fluorescence activated cell sorting cells displaying enhanced abilities antibodies. Based on analyses individual clones obtained from screen next-generation sequencing sorted libraries, distinct but partially overlapping sets amino acid substitutions conferring binding identified. These particularly enriched arginine highly conserved tryptophan residues. The UCA-binding also generally exhibited mature anti-MPER Mapping identified into available structures suggest they may act by destabilizing both initial pre-fusion conformation six-helix bundle involved fusion viral membranes, as well providing new or expanded epitopes accessibility