Structural basis for HIV-1 gp120 recognition by a germ-line version of a broadly neutralizing antibody
Creators
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1.
California Institute of Technology
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2.
Rockefeller University
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3.
Charité - University Medicine Berlin
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4.
Weizmann Institute of Science
Abstract
Efforts to design an effective antibody-based vaccine against HIV-1 would benefit from understanding how germ-line B-cell receptors (BCRs) recognize the HIV-1 gp120/gp41 envelope spike. Potent VRC01-like (PVL) HIV-1 antibodies derived from the VH1-2*02 germ-line allele target the conserved CD4 binding site on gp120. A bottleneck for design of immunogens capable of eliciting PVL antibodies is that VH1-2*02 germ-line BCR interactions with gp120 are uncharacterized. Here, we report the structure of a VH1-2*02 germ-line antibody alone and a germ-line heavy-chain/mature light-chain chimeric antibody complexed with HIV-1 gp120. VH1-2*02 residues make extensive contacts with the gp120 outer domain, including all PVL signature and CD4 mimicry interactions, but not critical CDRH3 contacts with the gp120 inner domain and bridging sheet that are responsible for the improved potency of NIH45-46 over closely related clonal variants, such as VRC01. Our results provide insight into initial recognition of HIV-1 by VH1-2*02 germ-line BCRs and may facilitate the design of immunogens tailored to engage and stimulate broad and potent CD4 binding site antibodies.
Additional Information
© 2013 National Academy of Sciences. Freely available online through the PNAS open access option. Contributed by Pamela J. Bjorkman, February 25, 2013 (sent for review February 11, 2013). Published online before print March 22, 2013. M.C.N. and P.J.B. are Howard Hughes Medical Institute Investigators. R.D. is incumbent of Tauro Career Development Chair in Biomedical Research. This research was supported by the International AIDS Vaccine Initiative and the Bill and Melinda Gates Foundation [Collaboration for AIDS Vaccine Discovery Grants 38619s (to M.C.N.) and 38660 (to P.J.B.) and Comprehensive Antibody-Vaccine Immune Monitoring Consortium Grant 1032144], NIAID [Grant P01AI100148 (to P.J.B. and M.C.N.; contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIAID or NIH)], the Enoch Foundation (R.D.) and the American Cancer Society (Grant PF-13-076-01-MPC to L.S.). The Molecular Observatory at Caltech is supported by the Gordon and Betty Moore Foundation. Operations at the Stanford Synchrotron Radiation Lightsource are supported by the US Department of Energy and the National Institutes of Health. Author contributions: L.S., P.J.B., and R.D. designed research; L.S., H.G., T.L., and R.D. performed research; A.P.W., J.F.S., and M.C.N. contributed new reagents/analytic tools; L.S., T.L., P.J.B., and R.D. analyzed data; and L.S., P.J.B., and R.D. wrote the paper.Attached Files
Published - PNAS-2013-Scharf-6049-54.pdf
Supplemental Material - pnas.201303682SI.pdf
Files
PNAS-2013-Scharf-6049-54.pdf
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Additional details
Identifiers
- PMCID
- PMC3625305
- Eprint ID
- 38842
- Resolver ID
- CaltechAUTHORS:20130606-150212765
Funding
- Howard Hughes Medical Institute (HHMI)
- International AIDS Vaccine Initiative
- Bill and Melinda Gates Foundation
- 38619s
- Bill and Melinda Gates Foundation
- 38660
- Bill and Melinda Gates Foundation
- 1032144
- NIH
- P01AI100148
- Enoch Foundation
- American Cancer Society
- PF-13-076-01-MPC
- Gordon and Betty Moore Foundation
- Department of Energy (DOE)
Dates
- Created
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2013-06-25Created from EPrint's datestamp field
- Updated
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2021-11-09Created from EPrint's last_modified field