Increasing the Potency and Breadth of an HIV Antibody by Using Structure-Based Rational Design

摘要

Antibodies against the CD4 binding site (CD4bs) on the HIV-1 spike protein gpl20 can show exceptional potency and breadth. We determined structures of NIH45-46, a more potent clonal variant of VRC01, alone and bound to gpl2O. Comparisons with VRC01-gpl20 revealed that a four-residue insertion in heavy chain complementarity-determining region 3 (CDRH3) contributed to increased interaction between NIH45-46 and the gpl20 inner domain, which correlated with enhanced neutralization. We used structure-based design to create NIH45-46~(G54W), a single substitution in CDRH2 that increases contact with the gpl2O bridging sheet and improves breadth and potency, critical properties for potential clinical use, by an order of magnitude. Together with the NIH45-46-gpl20 structure, these results indicate that gpl20 inner domain and bridging sheet residues should be included in immunogens to elicit CD4bs antibodies.