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Research Article

HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice

Joshua A. Horwitz, Ariel Halper-Stromberg, Hugo Mouquet, Alexander D. Gitlin, Anna Tretiakova, Thomas R. Eisenreich, Marine Malbec, Sophia Gravemann, Eva Billerbeck, Marcus Dorner, Hildegard Büning, Olivier Schwartz, Elena Knops, Rolf Kaiser, Michael S. Seaman, James M. Wilson, Charles M. Rice, Alexander Ploss, Pamela J. Bjorkman, Florian Klein, and Michel C. Nussenzweig
PNAS October 8, 2013 110 (41) 16538-16543; https://doi.org/10.1073/pnas.1315295110
Joshua A. Horwitz
aLaboratory of Molecular Immunology,
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Ariel Halper-Stromberg
aLaboratory of Molecular Immunology,
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Hugo Mouquet
aLaboratory of Molecular Immunology,
bLaboratory of Humoral Response to Pathogens, Department of Immunology and
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Alexander D. Gitlin
aLaboratory of Molecular Immunology,
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Anna Tretiakova
cDepartment of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104;
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Thomas R. Eisenreich
aLaboratory of Molecular Immunology,
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Marine Malbec
dDepartment of Virology, Virus and Immunity Unit, Institut Pasteur, 75015 Paris, France;
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Sophia Gravemann
eInstitute for Virology, German Center of Infection Research and Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany;
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Eva Billerbeck
fLaboratory of Virology and Infectious Diseases, and
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Marcus Dorner
fLaboratory of Virology and Infectious Diseases, and
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Hildegard Büning
eInstitute for Virology, German Center of Infection Research and Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany;
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Olivier Schwartz
dDepartment of Virology, Virus and Immunity Unit, Institut Pasteur, 75015 Paris, France;
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Elena Knops
eInstitute for Virology, German Center of Infection Research and Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany;
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Rolf Kaiser
eInstitute for Virology, German Center of Infection Research and Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany;
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Michael S. Seaman
gBeth Israel Deaconess Medical Center, Boston, MA 02215;
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James M. Wilson
cDepartment of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104;
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Charles M. Rice
fLaboratory of Virology and Infectious Diseases, and
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Alexander Ploss
fLaboratory of Virology and Infectious Diseases, and
hDepartment of Molecular Biology, Princeton University, Princeton, NJ 08544; and
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Pamela J. Bjorkman
iDivision of Biology and
jHoward Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125
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Florian Klein
aLaboratory of Molecular Immunology,
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Michel C. Nussenzweig
aLaboratory of Molecular Immunology,
kHoward Hughes Medical Institute, The Rockefeller University, New York, NY 10065;
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  • For correspondence: nussen@mail.rockefeller.edu
  1. Contributed by Michel C. Nussenzweig, August 14, 2013 (sent for review July 30, 2013)

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Significance

Treatment of HIV-1 infection in humans is achieved using combinations of highly effective antiretroviral therapy (ART) drugs to potently suppress viral replication and prevent the emergence of drug-resistant viruses. However, ART drugs must be taken indefinitely owing to rapid return of viremia upon termination of treatment. Highly potent broadly neutralizing antibodies (bNAbs) present a new potential therapeutic modality in the treatment of HIV-1 infection. Because of their comparatively longer half-lives relative to ART drugs and their ability to eliminate infected cells, bNAbs may alleviate some aspects of the lifelong treatment adherence burden of ART. Here we show that lowering the initial viral load with ART enables single bNAbs to effectively control an established HIV-1 infection in humanized mice.

Abstract

Effective control of HIV-1 infection in humans is achieved using combinations of antiretroviral therapy (ART) drugs. In humanized mice (hu-mice), control of viremia can be achieved using either ART or by immunotherapy using combinations of broadly neutralizing antibodies (bNAbs). Here we show that treatment of HIV-1–infected hu-mice with a combination of three highly potent bNAbs not only resulted in complete viremic control but also led to a reduction in cell-associated HIV-1 DNA. Moreover, lowering the initial viral load by coadministration of ART and immunotherapy enabled prolonged viremic control by a single bNAb after ART was withdrawn. Similarly, a single injection of adeno-associated virus directing expression of one bNAb produced durable viremic control after ART was terminated. We conclude that immunotherapy reduces plasma viral load and cell-associated HIV-1 DNA and that decreasing the initial viral load enables single bNAbs to control viremia in hu-mice.

  • CD4bs
  • glycan
  • gp160

Footnotes

  • ↵1F.K. and M.C.N. contributed equally to this work.

  • ↵2To whom correspondence should be addressed. E-mail: nussen{at}mail.rockefeller.edu.
  • Author contributions: J.A.H., O.S., P.J.B., F.K., and M.C.N. designed research; J.A.H., A.H.-S., H.M., A.D.G., T.R.E., M.M., E.B., M.D., E.K., R.K., M.S.S., and F.K. performed research; A.T., S.G., H.B., J.M.W., C.M.R., and A.P. contributed new reagents/analytic tools; J.A.H., A.H.-S., F.K., and M.C.N. analyzed data; and J.A.H. and M.C.N. wrote the paper.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1315295110/-/DCSupplemental.

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Durable HIV-1 control by bNAbs after stopping ART
Joshua A. Horwitz, Ariel Halper-Stromberg, Hugo Mouquet, Alexander D. Gitlin, Anna Tretiakova, Thomas R. Eisenreich, Marine Malbec, Sophia Gravemann, Eva Billerbeck, Marcus Dorner, Hildegard Büning, Olivier Schwartz, Elena Knops, Rolf Kaiser, Michael S. Seaman, James M. Wilson, Charles M. Rice, Alexander Ploss, Pamela J. Bjorkman, Florian Klein, Michel C. Nussenzweig
Proceedings of the National Academy of Sciences Oct 2013, 110 (41) 16538-16543; DOI: 10.1073/pnas.1315295110

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Durable HIV-1 control by bNAbs after stopping ART
Joshua A. Horwitz, Ariel Halper-Stromberg, Hugo Mouquet, Alexander D. Gitlin, Anna Tretiakova, Thomas R. Eisenreich, Marine Malbec, Sophia Gravemann, Eva Billerbeck, Marcus Dorner, Hildegard Büning, Olivier Schwartz, Elena Knops, Rolf Kaiser, Michael S. Seaman, James M. Wilson, Charles M. Rice, Alexander Ploss, Pamela J. Bjorkman, Florian Klein, Michel C. Nussenzweig
Proceedings of the National Academy of Sciences Oct 2013, 110 (41) 16538-16543; DOI: 10.1073/pnas.1315295110
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