Abstract
Strategies to combat HIV-1 require structural knowledge of envelope proteins from viruses in HIV-1 clade C, the most rapidly spreading subtype in the world. We present a 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 nonself antigen, and with CD4, an autoantigen. Binding studies using wild-type and mutant CD4 show 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 suggest a role for the gp120 V1V2 loop in creating a high-affinity, but slow-forming, epitope for 21c after CD4 binds. These results contribute to a molecular understanding of CD4-induced antibodies and provide the first visualization to our knowledge of a potentially autoreactive antibody Fab complexed with both self and nonself antigens.
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Acknowledgements
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.
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R.D. designed and performed crystallographic and binding experiments; P.M.M. produced Fabs; P.J.B. oversaw the project.
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Diskin, R., Marcovecchio, P. & Bjorkman, P. Structure of a clade C HIV-1 gp120 bound to CD4 and CD4-induced antibody reveals anti-CD4 polyreactivity. Nat Struct Mol Biol 17, 608–613 (2010). https://doi.org/10.1038/nsmb.1796
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DOI: https://doi.org/10.1038/nsmb.1796