TY - JOUR
T1 - Increasing the potency and breadth of an HIV antibody by using structure-based rational design
AU - Diskin, Ron
AU - Scheid, Johannes F.
AU - Marcovecchio, Paola M.
AU - West, Anthony P.
AU - Klein, Florian
AU - Gao, Han
AU - Gnanapragasam, Priyanthi N.P.
AU - Abadir, Alexander
AU - Seaman, Michael S.
AU - Nussenzweig, Michel C.
AU - Bjorkman, Pamela J.
N1 - Collaboration for AIDS Vaccine Discovery (CAVD); Bill and Melinda Gates Foundation [38660, 38619, 38619s]; NIH [P01 AI081677-01, RR00862, RR022220]; Molecular Observatory at Caltech; Gordon and Betty Moore Foundation; Sanofi-Aventis; German Research Foundation (DFG) [KL 2389/1-1]; U.S. Department of Energy
PY - 2011/12/2
Y1 - 2011/12/2
N2 - Antibodies against the CD4 binding site (CD4bs) on the HIV-1 spike protein gp120 can show exceptional potency and breadth. We determined structures of NIH45-46, a more potent clonal variant of VRC01, alone and bound to gp120. Comparisons with VRC01-gp120 revealed that a four-residue insertion in heavy chain complementarity-determining region 3 (CDRH3) contributed to increased interaction between NIH45-46 and the gp120 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 gp120 bridging sheet and improves breadth and potency, critical properties for potential clinical use, by an order of magnitude. Together with the NIH45-46-gp120 structure, these results indicate that gp120 inner domain and bridging sheet residues should be included in immunogens to elicit CD4bs antibodies.
AB - Antibodies against the CD4 binding site (CD4bs) on the HIV-1 spike protein gp120 can show exceptional potency and breadth. We determined structures of NIH45-46, a more potent clonal variant of VRC01, alone and bound to gp120. Comparisons with VRC01-gp120 revealed that a four-residue insertion in heavy chain complementarity-determining region 3 (CDRH3) contributed to increased interaction between NIH45-46 and the gp120 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 gp120 bridging sheet and improves breadth and potency, critical properties for potential clinical use, by an order of magnitude. Together with the NIH45-46-gp120 structure, these results indicate that gp120 inner domain and bridging sheet residues should be included in immunogens to elicit CD4bs antibodies.
UR - http://www.scopus.com/inward/record.url?scp=82755184131&partnerID=8YFLogxK
U2 - https://doi.org/10.1126/science.1213782
DO - https://doi.org/10.1126/science.1213782
M3 - مقالة
SN - 0036-8075
VL - 334
SP - 1289
EP - 1293
JO - Science
JF - Science
IS - 6060
ER -