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Published July 24, 2012 | Published + Supplemental Material
Journal Article Open

Structural basis for germ-line gene usage of a potent class of antibodies targeting the CD4-binding site of HIV-1 gp120

Abstract

A large number of anti–HIV-1 antibodies targeting the CD4-binding site (CD4bs) on the envelope glycoprotein gp120 have recently been reported. These antibodies, typified by VRC01, are remarkable for both their breadth and their potency. Crystal structures have revealed a common mode of binding for several of these antibodies; however, the precise relationship among CD4bs antibodies remains to be defined. Here we analyze existing structural and sequence data, propose a set of signature features for potent VRC01-like (PVL) antibodies, and verify the importance of these features by mutagenesis. The signature features explain why PVL antibodies derive from a single germ-line human V_H gene segment and why certain gp120 sequences are associated with antibody resistance. Our results bear on vaccine development and structure-based design to improve the potency and breadth of anti-CD4bs antibodies.

Additional Information

© 2012 by the National Academy of Sciences. Freely available online through the PNAS open access option. Contributed by Pamela J. Bjorkman, May 30, 2012 (sent for review May 2, 2012). Published online before print June 27, 2012. We thank the Caltech Protein Expression Center, Terri Lee, Paola Marcovecchio, Tim Feliciano, Gloria Tran, and Han Gao for DNA preparation, protein expression, and purification; Jost Vielmetter for assistance with Biacore experiments; Johannes Scheid, Florian Klein, and Ari Halper-Stromberg for helpful discussions and reagents; Grace Aldrovandi and Kyle Nakamura for helpful discussions; and Thiago Olivera for help with the data for Fig. S2. This project was supported by Award DP1OD006961 (to P.J.B.) from the Office of The Director, National Institutes of Health. This work was also supported by Collaboration for AIDS Vaccine Discovery grants with support from the Bill and Melinda Gates Foundation [Grant 38660 (to P.J.B.) and Grant 38619s (to M.C.N.)]. Author contributions: A.P.W. designed and performed research; A.P.W., R.D., and P.J.B. analyzed data; and A.P.W., M.C.N., and P.J.B. wrote the paper. The authors declare no conflict of interest.

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Published - PNAS-2012-West-E2083-90.pdf

Supplemental Material - pnas.201208984SI.pdf

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