Increasing the Potency and Breadth of an HIV Antibody by Using Structure-Based Rational Design
Abstract
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.
Additional Information
© 2011 American Association for the Advancement of Science. Received for publication 9 September 2011. Accepted for publication 18 October 2011. We thank B. Hahn, J. Baalwa, F. McCutchan, G. Shaw, D. Montefiori, M. Thomson, J. Overbaugh, R. Swanstrom, L. Morris, J. Kim, L. Zhang, D. Ellenberger, and C. Williamson for contributing the HIV-1 envelope plasmids used in our neutralization panel; the Caltech Protein Expression Center; T. Oliveira and A. Halper-Stromberg for calculations and helpful discussions; and members of the Bjorkman and Nussenzweig laboratories for critical reading of the manuscript. R.D., J.F.S., M.C.N., and P.J.B. have pending patent applications with the U.S. Patent and Trademark Office, patent numbers U.S. 61/486,960 and 61/523,244, titled "Human immunodeficiency virus neutralizing antibodies and methods of use thereof" and "Anti-HIV antibodies and related methods and compositions," respectively. The reagents are available with a Materials Transfer Agreement. This work was supported by Collaboration for AIDS Vaccine Discovery (CAVD) grants with support from the Bill and Melinda Gates Foundation [grant 38660 (P.J.B.), grant 38619 (M.S.S.) and grant 38619s (M.C.N.)]; NIH grants P01 AI081677-01 (M.C.N.), RR00862, and RR022220; and the Molecular Observatory at Caltech, supported by the Gordon and Betty Moore Foundation and the Sanofi-Aventis Bioengineering Research Program. F.K. was supported by the German Research Foundation (DFG, KL 2389/1-1). Operations at Stanford Synchrotron Radiation Lightsource are supported by the U.S. Department of Energy and NIH. The data reported in this paper are tabulated in the main text and the supporting online material, and coordinates and x-ray crystallographic data for the NIH45-46–gp120 complex and NIH45-46 Fab have been deposited in the PDB (accession codes 3U7Y and 3U7W, respectively).Attached Files
Accepted Version - nihms-333322.pdf
Supplemental Material - Diskin.SOM.rev1.pdf
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Additional details
- PMCID
- PMC3232316
- Eprint ID
- 28529
- Resolver ID
- CaltechAUTHORS:20111220-092937610
- Collaboration for AIDS Vaccine Discovery
- 38660
- Bill and Melinda Gates Foundation
- 38619
- Bill and Melinda Gates Foundation
- 38619s
- Bill and Melinda Gates Foundation
- P01 AI081677-01
- NIH
- RR00862
- NIH
- RR022220
- NIH
- Caltech Molecular Observatory
- Gordon and Betty Moore Foundation
- Sanofi-Aventis Bioengineering Research Program
- KL 2389/1-1
- Deutsche Forschungsgemeinschaft (DFG)
- Department of Energy (DOE)
- Created
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2011-12-20Created from EPrint's datestamp field
- Updated
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2021-11-09Created from EPrint's last_modified field