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

Florian Klein; Ariel Halper-Stromberg; Joshua A. Horwitz; Henning Gruell; Johannes F. Scheid; Stylianos Bournazos; Hugo Mouquet; Linda A. Spatz; Ron Diskin; Alexander Abadir; Trinity Zang; Marcus Dorner; Eva Billerbeck; Rachael N. Labitt; Christian Gaebler; Paola M. Marcovecchio; Reha Baris Incesu; Thomas R. Eisenreich; Paul D. Bieniasz; Michael S. Seaman1; Pamela J. Bjorkman; Jeffrey V. Ravetch; Alexander Ploss; Michel C. Nussenzweig

doi:10.1038/nature11604

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

Florian Klein, Ariel Halper-Stromberg, Joshua A. Horwitz, Henning Gruell, Johannes F. Scheid, Stylianos Bournazos, Hugo Mouquet, Linda A. Spatz, Ron Diskin, Alexander Abadir, Trinity Zang, Marcus Dorner, Eva Billerbeck, Rachael N. Labitt, Christian Gaebler, Paola M. Marcovecchio, Reha Baris Incesu, Thomas R. Eisenreich, Paul D. Bieniasz, Michael S. Seaman1Pamela J. Bjorkman, Jeffrey V. Ravetch, Alexander Ploss, Michel C. Nussenzweig

Research output: Contribution to journal › Letter › peer-review

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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 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 60days 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.

Original language	English (US)
Pages (from-to)	118-122
Number of pages	5
Journal	Nature
Volume	492
Issue number	7427
DOIs	https://doi.org/10.1038/nature11604
State	Published - Dec 6 2012
Externally published	Yes

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Klein, F., Halper-Stromberg, A., Horwitz, J. A., Gruell, H., Scheid, J. F., Bournazos, S., Mouquet, H., Spatz, L. A., Diskin, R., Abadir, A., Zang, T., Dorner, M., Billerbeck, E., Labitt, R. N., Gaebler, C., Marcovecchio, P. M., Incesu, R. B., Eisenreich, T. R., Bieniasz, P. D., ... Nussenzweig, M. C. (2012). HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature, 492(7427), 118-122. https://doi.org/10.1038/nature11604

Klein, F, Halper-Stromberg, A, Horwitz, JA, Gruell, H, Scheid, JF, Bournazos, S, Mouquet, H, Spatz, LA, Diskin, R, Abadir, A, Zang, T, Dorner, M, Billerbeck, E, Labitt, RN, Gaebler, C, Marcovecchio, PM, Incesu, RB, Eisenreich, TR, Bieniasz, PD, Seaman1, MS, Bjorkman, PJ, Ravetch, JV, Ploss, A & Nussenzweig, MC 2012, 'HIV therapy by a combination of broadly neutralizing antibodies in humanized mice', Nature, vol. 492, no. 7427, pp. 118-122. https://doi.org/10.1038/nature11604

@article{65dbe1b0cc9a40c99d00e3d92d0d97c4,

title = "HIV therapy by a combination of broadly neutralizing antibodies in humanized mice",

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 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 60days 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.",

author = "Florian Klein and Ariel Halper-Stromberg and Horwitz, {Joshua A.} and Henning Gruell and Scheid, {Johannes F.} and Stylianos Bournazos and Hugo Mouquet and Spatz, {Linda A.} and Ron Diskin and Alexander Abadir and Trinity Zang and Marcus Dorner and Eva Billerbeck and Labitt, {Rachael N.} and Christian Gaebler and Marcovecchio, {Paola M.} and Incesu, {Reha Baris} and Eisenreich, {Thomas R.} and Bieniasz, {Paul D.} and Seaman1, {Michael S.} and Bjorkman, {Pamela J.} and Ravetch, {Jeffrey V.} and Alexander Ploss and Nussenzweig, {Michel C.}",

note = "Funding Information: 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 TrademarkOffice.These reagents are available witha MaterialTransfer 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{\textquoteright}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.",

year = "2012",

month = dec,

day = "6",

doi = "10.1038/nature11604",

language = "English (US)",

volume = "492",

pages = "118--122",

journal = "Nature",

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TY - JOUR

T1 - HIV therapy by a combination of broadly neutralizing antibodies in humanized mice

AU - Klein, Florian

AU - Halper-Stromberg, Ariel

AU - Horwitz, Joshua A.

AU - Gruell, Henning

AU - Scheid, Johannes F.

AU - Bournazos, Stylianos

AU - Mouquet, Hugo

AU - Spatz, Linda A.

AU - Diskin, Ron

AU - Abadir, Alexander

AU - Zang, Trinity

AU - Dorner, Marcus

AU - Billerbeck, Eva

AU - Labitt, Rachael N.

AU - Gaebler, Christian

AU - Marcovecchio, Paola M.

AU - Incesu, Reha Baris

AU - Eisenreich, Thomas R.

AU - Bieniasz, Paul D.

AU - Seaman1, Michael S.

AU - Bjorkman, Pamela J.

AU - Ravetch, Jeffrey V.

AU - Ploss, Alexander

AU - Nussenzweig, Michel C.

N1 - Funding Information: 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 TrademarkOffice.These reagents are available witha MaterialTransfer 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.

PY - 2012/12/6

Y1 - 2012/12/6

N2 - 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 60days 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.

AB - 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 60days 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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U2 - 10.1038/nature11604

DO - 10.1038/nature11604

M3 - Letter

C2 - 23103874

AN - SCOPUS:84870562234

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VL - 492

SP - 118

EP - 122

JO - Nature

JF - Nature

IS - 7427

ER -

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

Abstract

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