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HIV therapy by a combination of broadly neutralizing antibodies in humanized mice

Klein, Florian and Halper-Stromberg, Ariel and Horwitz, Joshua A. and Gruell, Henning and Scheid, Johannes F. and Bournazos, Stylianos and Mouquet, Hugo and Spatz, Linda A. and Diskin, Ron and Abadir, Alexander and Zang, Trinity and Dorner, Marcus and Billerbeck, Eva and Labitt, Rachael N. and Gaebler, Christian and Marcovecchio, Paola M. and Incesu, Reha-Baris and Eisenreich, Thomas R. and Bieniasz, Paul D. and Seaman, Michael S. and Bjorkman, Pamela J. and Ravetch, Jeffrey V. and Ploss, Alexander and Nussenzweig, Michel C. (2012) HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature, 492 (7427). pp. 118-122. ISSN 0028-0836. PMCID PMC3809838. doi:10.1038/nature11604.

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Human antibodies to human immunodeficiency virus-1 (HIV-1) can neutralize a broad range of viral isolates in vitro and protect non-human primates against infection. Previous work showed that antibodies exert selective pressure on the virus but escape variants emerge within a short period of time. However, these experiments were performed before the recent discovery of more potent anti-HIV-1 antibodies and their improvement by structure-based design. Here we re-examine passive antibody transfer as a therapeutic modality in HIV-1-infected humanized mice. Although HIV-1 can escape from antibody monotherapy, combinations of broadly neutralizing antibodies can effectively control HIV-1 infection and suppress viral load to levels below detection. Moreover, in contrast to antiretroviral therapy the longer half-life of antibodies led to control of viraemia for an average of 60 days after cessation of therapy. Thus, combinations of potent monoclonal antibodies can effectively control HIV-1 replication in humanized mice, and should be re-examined as a therapeutic modality in HIV-1-infected individuals.

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Diskin, Ron0000-0002-2837-5897
Bjorkman, Pamela J.0000-0002-2277-3990
Nussenzweig, Michel C.0000-0003-0592-8564
Additional Information:© 2012 Macmillan Publishers Limited. Received 21 May; accepted 20 September 2012; Published online 24 October 2012. We thank R. Kaiser for analysing viral loads of reference HIV-1 samples and N. N. Freund for producing YU2 gp120. We thank B. Flatley, T. Friling, H. Gao, S. Sell and S. Hinklein for assistance and technical support, M. Suarez-Farinas for advice on statistical analysis, and M. Babayeva for helping with antibody t1/2 estimation. M.C.N. and F.K. have a pending patent application for the antibody 3BC176 and M.C.N., P.J.B. and H.M. for the antibody 10-1074 with the United States Patent and Trademark Office.These reagents are available with aMaterial Transfer Agreement. F.K. (KL 2389/1-1), M.D. (DO 1450/1-1) and E.B. (BI 1422/1-1) were supported by the German Research Foundation (DFG). H.G., C.G. and R.-B.I. were supported by The German National Academic Foundation. M.S.S. was supported by the Bill and Melinda Gates Foundation’s Comprehensive Antibody Vaccine Immune Monitoring Consortium, grant number 1032144. A.P. is a recipient of a Liver Scholar Award from the American Liver Foundation. This work was supported in part by CAVD grant OPP1033115 from the Bill and Melinda Gates Foundation to M.C.N., in part by NIAID 1UM1AI100663 to M.C.N. and NIH grant AI081677 to M.C.N. M.C.N., P.J.B. and P.D.B. are HHMI investigators. Author Contributions: F.K., A.H.-S. and J.A.H. planned and performed experiments and wrote the manuscript. H.G., J.F.H., S.B., H.M., L.A.S., R.D., A.A., T.Z., M.D., E.B., R.N.L., C.G., P.M.M., R.-B.I., T.R.E. and M.S.S. performed experiments. P.D.B., P.J.B., J.V.R. and A.P. provided reagents, advice and edited themanuscript. M.C.N. planned experiments and wrote the manuscript.
Funding AgencyGrant Number
Deutsche Forschungsgemeinschaft (DFG)KL 2389/1-1
Deutsche Forschungsgemeinschaft (DFG)DO 1450/1-1
Deutsche Forschungsgemeinschaft (DFG)BI 1422/1-1
Studienstiftung des deutschen VolkesUNSPECIFIED
Bill and Melinda Gates Foundation1032144
American Liver FoundationUNSPECIFIED
Bill and Melinda Gates FoundationOPP1033115
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Subject Keywords:Immunology; Medical research; Virology; Disease
Issue or Number:7427
PubMed Central ID:PMC3809838
Record Number:CaltechAUTHORS:20130103-133212476
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:36151
Deposited By: Jason Perez
Deposited On:03 Jan 2013 23:57
Last Modified:09 Nov 2021 23:20

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