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Broad neutralization coverage of HIV by multiple highly potent antibodies

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Abstract

Broadly neutralizing antibodies against highly variable viral pathogens are much sought after to treat or protect against global circulating viruses. Here we probed the neutralizing antibody repertoires of four human immunodeficiency virus (HIV)-infected donors with remarkably broad and potent neutralizing responses and rescued 17 new monoclonal antibodies that neutralize broadly across clades. Many of the new monoclonal antibodies are almost tenfold more potent than the recently described PG9, PG16 and VRC01 broadly neutralizing monoclonal antibodies and 100-fold more potent than the original prototype HIV broadly neutralizing monoclonal antibodies1,2,3. The monoclonal antibodies largely recapitulate the neutralization breadth found in the corresponding donor serum and many recognize novel epitopes on envelope (Env) glycoprotein gp120, illuminating new targets for vaccine design. Analysis of neutralization by the full complement of anti-HIV broadly neutralizing monoclonal antibodies now available reveals that certain combinations of antibodies should offer markedly more favourable coverage of the enormous diversity of global circulating viruses than others and these combinations might be sought in active or passive immunization regimes. Overall, the isolation of multiple HIV broadly neutralizing monoclonal antibodies from several donors that, in aggregate, provide broad coverage at low concentrations is a highly positive indicator for the eventual design of an effective antibody-based HIV vaccine.

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Figure 1: Neutralization activity of the newly identified PGT antibodies.
Figure 2: Key monoclonal antibodies fully recapitulate serum neutralization by the corresponding donor serum.
Figure 3: Epitope mapping of PGT antibodies.
Figure 4: Certain antibodies or antibody combinations are able to cover a broad range of HIV isolates at low, vaccine-achievable concentrations.

Accession codes

Primary accessions

GenBank/EMBL/DDBJ

Data deposits

Gene sequences of the reported antibodies and the primers used for antibody isolation have been deposited under GenBank accession numbers JN201894–JN201927.

Change history

  • 22 September 2011

    Minor text changes were made to paragraph beginning, 'The potency and breadth of the monoclonal antibodies...', Acknowledgements and Author Contributions.

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Acknowledgements

We thank N. Schultz, K. Le and V. Thaney for technical assistance at The Scripps Research Institute. We also thank C. Corbaci, S. M. Eagol and C. Williams for assistance with Fig. 3. We would also like to thank the research staff members of the Theraclone I-STAR Discovery and Antibody Purification Team, and K. Limoli, S. Jauregui, K. Tran, P. Sitou, J. Perea, B. Huang and P. Guinto at Monogram BioSciences. We thank R. McBride for assistance with the glycan array and are grateful to W. Olson for providing purified KNH1144 SOSIP trimer, R. Wyatt for providing the YU2 Foldon trimer and J. Mascola for providing monoclonal antibody VRC01. In addition, we would like to thank all of the International AIDS Vaccine Initiative (IAVI) Protocol G project, clinical and site team members, the IAVI Human Immunology Laboratory (HIL) and all of the Protocol G clinical investigators, specifically, G. Miiro, A. Pozniak, D. McPhee, O. Manigart, E. Karita, A. Inwoley, W. Jaoko, J. DeHovitz, L.-G. Bekker, P. Pitisuttithum, R. Paris, J. Serwanga and S. Allen. This work was supported by IAVI, NIAID, the Ragon Institute and the United States for International Development (USAID). The contents are the responsibility of the authors and do not necessarily reflect the views of USAID or the United States Government.

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Contributions

Project planning was performed by L.M.W., M.H., K.J.D., E.F., P.-Y.C.-H., R.P., J-P.J., T.W., S.P., M.D.S., W.K., I.A.W., M.M., S.F., D.R.B. and P.P.; experimental work by L.M.W., M.H., K.J.D., E.F., R.P., J.-P. J., P.-Y.C.-H., S.-K.W., A.R., J.L.M., P.W.H., O.A.O. and T.W.; data analysis by M.H., L.M.W., K.J.D., E.F., T.W., P.-Y.C.-H., D.R.B. and P.P.; composition of the first draft of the manuscript by L.M.W. and D.R.B.; manuscript layout and major manuscript revisions by M.H., K.J.D. and P.P.; revisions by R.P., J.-P.J., E.F., W.C.K. and I.A.W.

Corresponding authors

Correspondence to Dennis R. Burton or Pascal Poignard.

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Competing interests

Po-Ying Chan-Hui, Jennifer Mitcham, Ole Olsen, Matthew Moyle, Sanjay Phogat, Pascal Poignard, Melissa Simek, Wayne Koff, Laura M. Walker and Dennis R. Burton are inventors on a patent describing the PGT antibodies. 1.PGT 127, 128, 131, 139, 145 Antibodies US 61/476,978: US provisional application filed in 4/10/11 2. PGT 127, 128, 131, 139, 145 Antibodies US 61/476,978: US provisional application filed in 4/10/11.

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This file contains Supplementary Tables 1-6, Supplementary Figures 1-8 with legends and Supplementary Notes. (PDF 2999 kb)

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Walker, L., Huber, M., Doores, K. et al. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 477, 466–470 (2011). https://doi.org/10.1038/nature10373

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