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Computational analysis of anti-HIV-1 antibody neutralization panel data to identify potential functional epitope residues

West, Anthony P., Jr. and Scharf, Louise and Horwitz, Joshua and Klein, Florian and Nussenzweig, Michel C. and Bjorkman, Pamela J. (2013) Computational analysis of anti-HIV-1 antibody neutralization panel data to identify potential functional epitope residues. Proceedings of the National Academy of Sciences of the United States of America, 110 (26). pp. 10598-10603. ISSN 0027-8424. PMCID PMC3696754. doi:10.1073/pnas.1309215110.

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Advances in single-cell antibody cloning methods have led to the identification of a variety of broadly neutralizing anti–HIV-1 antibodies. We developed a computational tool (Antibody Database) to help identify critical residues on the HIV-1 envelope protein whose natural variation affects antibody activity. Our simplifying assumption was that, for a given antibody, a significant portion of the dispersion of neutralization activity across a panel of HIV-1 strains is due to the amino acid identity or glycosylation state at a small number of specific sites, each acting independently. A model of an antibody’s neutralization IC_(50) was developed in which each site contributes a term to the logarithm of the modeled IC_(50). The analysis program attempts to determine the set of rules that minimizes the sum of the residuals between observed and modeled IC_(50) values. The predictive quality of the identified rules may be assessed in part by whether there is support for rules within individual viral clades. As a test case, we analyzed antibody 8ANC195, an anti-glycoprotein gp120 antibody of unknown specificity. The model for this antibody indicated that several glycosylation sites were critical for neutralization. We evaluated this prediction by measuring neutralization potencies of 8ANC195 against HIV-1 in vitro and in an antibody therapy experiment in humanized mice. These experiments confirmed that 8ANC195 represents a distinct class of glycan-dependent anti–HIV-1 antibody and validated the utility of computational analysis of neutralization panel data.

Item Type:Article
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URLURL TypeDescription DOIArticle CentralArticle
Nussenzweig, Michel C.0000-0003-0592-8564
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2013 National Academy of Sciences. Freely available online through the PNAS open access option. Contributed by Pamela J. Bjorkman, May 15, 2013 (sent for review April 18, 2013). We thank the Jost Vielmetter and the Caltech Protein Expression Center, Tim Feliciano, Lilian Nogueira, and Han Gao for protein expression and purification, Terri Lee and Priyanthi Gnanapragasam for mutagenesis and neutralization assays, and Hugo Mouquet, Bette Korber, Kyle Nakamura, and Vanessa Jonsson for helpful discussions. We also thank Alexander Ploss for help in generating humanized mice. This work was supported by a Collaboration for AIDS Vaccine Discovery grant from The Bill and Melinda Gates Foundation (Grant ID 1040753) (to P.J.B. and M.C.N.), National Institutes of Health (NIH) Grant HIVRAD P01 AI100148 (to P.J.B. and M.C.N.) and Award DP1OD006961 (to P.J.B.), NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery Grant 1UM1 AI100663-01 (to M.C.N.), and American Cancer Society Grant PF-13-076-01-MPC (to L.S.). F.K. was supported by The Stavros Niarchos Foundation. Author contributions: A.P.W., L.S., M.C.N., and P.J.B. designed research; A.P.W., L.S., J.H., and F.K. performed research; A.P.W. contributed new reagents/analytic tools; A.P.W., L.S., J.H., and F.K. analyzed data; and A.P.W., L.S., M.C.N., and P.J.B. wrote the paper.
Funding AgencyGrant Number
Bill and Melinda Gates Foundation1040753
NIH1UM1 AI100663-01
American Cancer SocietyPF-13-076-01-MPC
Stavros Niarchos FoundationUNSPECIFIED
Issue or Number:26
PubMed Central ID:PMC3696754
Record Number:CaltechAUTHORS:20130815-105910867
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Official Citation:Anthony P. West, Jr., Louise Scharf, Joshua Horwitz, Florian Klein, Michel C. Nussenzweig, and Pamela J. Bjorkman Computational analysis of anti–HIV-1 antibody neutralization panel data to identify potential functional epitope residues PNAS 2013 110 (26) 10598-10603; published ahead of print June 10, 2013, doi:10.1073/pnas.1309215110
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:39951
Deposited By: Tony Diaz
Deposited On:16 Aug 2013 19:58
Last Modified:09 Nov 2021 23:48

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