Restricting HIV-1 pathways for escape using rationally designed anti–HIV-1 antibodies
Abstract
Recently identified broadly neutralizing antibodies (bNAbs) that potently neutralize most HIV-1 strains are key to potential antibody-based therapeutic approaches to combat HIV/AIDS in the absence of an effective vaccine. Increasing bNAb potencies and resistance to common routes of HIV-1 escape through mutation would facilitate their use as therapeutics. We previously used structure-based design to create the bNAb NIH45-46G54W, which exhibits superior potency and/or breadth compared with other bNAbs. We report new, more effective NIH45-46^(G54W) variants designed using analyses of the NIH45-46–gp120 complex structure and sequences of NIH45-46^(G54W)–resistant HIV-1 strains. One variant, 45-46m2, neutralizes 96% of HIV-1 strains in a cross-clade panel and viruses isolated from an HIV-infected individual that are resistant to all other known bNAbs, making it the single most broad and potent anti–HIV-1 antibody to date. A description of its mechanism is presented based on a 45-46m2–gp120 crystal structure. A second variant, 45-46m7, designed to thwart HIV-1 resistance to NIH45-46G54W arising from mutations in a gp120 consensus sequence, targets a common route of HIV-1 escape. In combination, 45-46m2 and 45-46m7 reduce the possible routes for the evolution of fit viral escape mutants in HIV-1_(YU-2)–infected humanized mice, with viremic control exhibited when a third antibody, 10–1074, was added to the combination.
Additional Information
© 2013 The Rockefeller University Press. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). Submitted: 30 January 2013; Accepted: 1 May 2013. We thank B. Hahn, 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, Alexander Ploss and Charles M Rice for providing mice for therapy experiments, the Caltech Protein Expression Center, and members of the Bjorkman laboratory for critical reading of the manuscript. R. Diskin, A.P. West, M.C. Nussenzweig, and P.J. Bjorkman have pending patent applications with the U.S. Patent and Trademark Office, patent numbers U.S. CIT- 5930-P3 and CIT-6235-P, titled "Improving the Potency and Breadth of Anti-HIV Antibodies–NIH45-46S28Y(LC) with NIH45-46G54W(HC)" and "Overcoming HIV Pathways for Escape using Rationally Designed Anti-HIV Antibodies," respectively. The reagents are available with a Materials Transfer Agreement. R. Diskin is the Tauro Career Development Chair in Biomedical Research. This work was supported by Collaboration for AIDS Vaccine Discovery (CAVD) grants with support from the Bill and Melinda Gates Foundation (grant 1040753 to P.J. Bjorkman and grant 1032144 to M.S. Seaman); the NIAID of the National Institutes of Health under Award numbers P01AI100148 (P.J. Bjorkman and M.C. Nussenzweig) and UM1AI100663 (M.C. Nussenzweig); NIH grant R01AI081625 (L. Stamatatos)—the content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH; and the Molecular Observatory at Caltech supported by the Gordon and Betty Moore Foundation. Operations at Stanford Synchrotron Radiation Lightsource are supported by the U.S. Department of Energy and NIH. Coordinates and x-ray crystallographic data for the 45-46m2/gp120 complex have been deposited in the PDB under accession code 4JKP. The authors declare no competing financial interests. Author contributions: R. Diskin, M.C. Nussenzweig, and P.J. Bjorkman conceived the study, R. Diskin performed structural determinations, analyses, and design, P.M. Marcovecchio and H. Gao produced and purified proteins, T. Lee, M.S. Seaman, D.N. Sather and L. Stamatatos performed neutralization assays, D.N. Sather and L. Stamatatos performed viral replication analysis, F. Klein, A. Halper-Stromberg, and J.A. Horwitz performed in vivo therapy experiments and analyzed escape mutants, A.P. West helped with data analysis, and R. Diskin and P.J. Bjorkman wrote the paper with contributions from all coauthors.Attached Files
Published - J_Exp_Med-2013-Diskin-1235-49.pdf
Supplemental Material - JEM_20130221_sm.pdf
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Additional details
- PMCID
- PMC3674693
- Eprint ID
- 39326
- Resolver ID
- CaltechAUTHORS:20130711-154054415
- Collaboration for AIDS Vaccine Discovery
- 1040753
- Bill and Melinda Gates Foundation
- 1032144
- Bill and Melinda Gates Foundation
- P01AI100148
- NIH
- UM1AI100663
- NIH
- R01AI081625
- NIH
- Caltech Molecular Observatory
- Gordon and Betty Moore Foundation
- Department of Energy (DOE)
- Created
-
2013-07-15Created from EPrint's datestamp field
- Updated
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2021-11-09Created from EPrint's last_modified field