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

Nature volume 492, pages 118–122 (2012)Cite this article

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Abstract

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 infection1,2. Previous work showed that antibodies exert selective pressure on the virus but escape variants emerge within a short period of time3,4. However, these experiments were performed before the recent discovery of more potent anti-HIV-1 antibodies and their improvement by structure-based design5,6,7,8,9. 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 therapy10,11,12, 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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Figure 1: Monotherapy using broadly neutralizing antibodies in HIV-1 YU2 -infected humanized mice.
Figure 2: HIV therapy by a combination of three (tri-mix) or five (penta-mix) broadly neutralizing antibodies in HIV-1 YU2 -infected humanized mice.
Figure 3: Viral rebound in HIV-1 YU2 -infected humanized mice after cessation of antibody therapy.

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Acknowledgements

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 a Material 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.

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Author notes

  1. Ariel Halper-Stromberg and Joshua A. Horwitz: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Molecular Immunology, The Rockefeller University, New York, 10065, New York, USA

    Florian Klein, Ariel Halper-Stromberg, Joshua A. Horwitz, Henning Gruell, Johannes F. Scheid, Hugo Mouquet, Linda A. Spatz, Alexander Abadir, Christian Gaebler, Reha-Baris Incesu, Thomas R. Eisenreich & Michel C. Nussenzweig

  2. Medizinische Fakultät, Westfälische Wilhelms-Universität Münster, D-48149 Münster, Germany,

    Henning Gruell

  3. Charité Universitätsmedizin, Berlin, D-10117, Germany

    Johannes F. Scheid

  4. Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, 10065, New York, USA

    Stylianos Bournazos & Jeffrey V. Ravetch

  5. Department of Microbiology and Immunology, Sophie Davis School of Biomedical Education, The City College of New York, New York, 10031, New York, USA

    Linda A. Spatz

  6. Division of Biology, California Institute of Technology, Pasadena, 91125, California, USA

    Ron Diskin, Paola M. Marcovecchio & Pamela J. Bjorkman

  7. Aaron Diamond AIDS Research Center, Laboratory of Retrovirology, The Rockefeller University, New York, 10065, New York, USA

    Trinity Zang & Paul D. Bieniasz

  8. Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, 10065, New York, USA

    Marcus Dorner, Eva Billerbeck, Rachael N. Labitt & Alexander Ploss

  9. Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, D-01307, Germany

    Christian Gaebler

  10. Howard Hughes Medical Institute, The Rockefeller University, New York, 10065, New York, USA

    Paul D. Bieniasz & Michel C. Nussenzweig

  11. Beth Israel Deaconess Medical Center, Boston, 02215, Massachusetts, USA

    Michael S. Seaman

  12. Howard Hughes Medical Institute, California Institute of Technology, Pasadena, 91125, California, USA

    Pamela J. Bjorkman

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  1. Florian Klein
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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 the manuscript. M.C.N. planned experiments and wrote the manuscript.

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Correspondence to Michel C. Nussenzweig.

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Klein, F., Halper-Stromberg, A., Horwitz, J. et al. HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature 492, 118–122 (2012). https://doi.org/10.1038/nature11604

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