Structure of a clade C HIV-1 gp120 bound to CD4 and CD4-induced antibody reveals anti-CD4 polyreactivity
Abstract
Strategies to combat HIV-1 require structural knowledge of envelope proteins from clade C viruses, the most common in the world. We present the first crystal structure containing a clade C gp120 envelope. The structure, a complex between gp120, the host receptor CD4, and the CD4-induced antibody 21c, reveals that the 21c epitope involves contacts with gp120, a non-self antigen, and with CD4, an auto-antigen. Binding studies using wild-type and mutant CD4 showed that 21c Fab binds CD4 in the absence of gp120, and that binding of 21c to clade C and HIV-2 gp120s requires the crystallographically-observed 21c-CD4 interaction. Additional binding data suggested a role for the gp120 V1V2 loop in creating a high-affinity, but slow-forming, epitope for 21c after CD4 binds. This study represents the first visualization of a potentially autoreactive antibody Fab complexed with both self and non-self antigens.
Additional Information
© 2010 Nature America, Inc. Received 06 January 2010. Accepted 24 February 2010. Published online 31 March 2010. We thank R. Strong for suggesting the sCD4 mutant experiments, I. Nangiana and the Caltech Protein Expression Center for expressing proteins in insect cells, Y. Wu for testing for tyrosine sulfation on 21c, R. Galimidi and M. Politzer for technical assistance, M. Murphy for help with figures, and D. Baltimore, L. Stamatatos and A. West for critical reading of the manuscript. This work was supported by a fellowship from the European Molecular Biology Organization (R.D.), a Collaboration for AIDS Vaccine Discovery (CAVD) grant with support from the Bill & Melinda Gates Foundation (Grant 38660; PI: L. Stamatatos) (P.J.B.), and the Molecular Observatory at Caltech supported by the Gordon and Betty Moore Foundation. Operations at Stanford Synchrotron Radiation Lightsource are supported by the US Department of Energy and the US National Institutes of Health. Author Contributions: R.D. designed and performed crystallographic and binding experiments; P.M.M. produced Fabs; P.J.B. oversaw the project. Accession codes. Protein Data Bank: Coordinates and associated structure factors have been deposited with accession codes 3LMJ (21c Fab alone) and 3LQA (CAP210–sCD4–21c complex). The authors declare no competing financial interests.Attached Files
Accepted Version - nihms223190.pdf
Supplemental Material - nsmb.1796-S1.pdf
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Additional details
- PMCID
- PMC2949298
- Eprint ID
- 18533
- Resolver ID
- CaltechAUTHORS:20100602-151224902
- European Molecular Biology Organization (EMBO)
- 38660
- Bill and Melinda Gates Foundation
- Gordon and Betty Moore Foundation
- Department of Energy (DOE)
- NIH
- Howard Hughes Medical Institute (HHMI)
- Created
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2010-06-23Created from EPrint's datestamp field
- Updated
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2021-11-08Created from EPrint's last_modified field