Abstract

Human immunodeficiency virus type 1 (HIV-1)-specific monoclonal antibodies with extraordinary potency and breadth have recently been described. In humanized mice, combinations of monoclonal antibodies have been shown to suppress viraemia, but the therapeutic potential of these monoclonal antibodies has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific monoclonal antibodies, as well as the single glycan-dependent monoclonal antibody PGT121, resulted in a rapid and precipitous decline of plasma viraemia to undetectable levels in rhesus monkeys chronically infected with the pathogenic simian–human immunodeficiency virus SHIV-SF162P3. A single monoclonal antibody infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa and lymph nodes without the development of viral resistance. Moreover, after monoclonal antibody administration, host Gag-specific T-lymphocyte responses showed improved functionality. Virus rebounded in most animals after a median of 56 days when serum monoclonal antibody titres had declined to undetectable levels, although, notably, a subset of animals maintained long-term virological control in the absence of further monoclonal antibody infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of monoclonal antibody therapy for HIV-1 in humans.

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Acknowledgements

We thank A. Brinkman, M. Ferguson, C. Gittens, R. Geleziunas, R. Hamel, K. Kelly, J. Kramer, A. McNally, D. Montefiori, L. Nogueira, L. Parenteau, M. Pensiero, L. Peter, M. Shetty, D. Sok, K. Stanley, F. Stephens, W. Wagner, B. Walker, A. West and J. Yalley-Ogunro for advice, assistance and reagents. The SIVmac239 Gag peptide pool was obtained from the NIH AIDS Research and Reference Reagent Program. We acknowledge support from the National Institutes of Health (AI055332, AI060354, AI078526, AI084794, AI095985, AI096040, AI10063, AI100148, AI100663); the Bill and Melinda Gates Foundation (OPP1033091, OPP1033115, OPP1040741, OPP1040753); the Ragon Institute of MGH, MIT, and Harvard; the Lundbeck Foundation; and the Stavros Niarchos Foundation. M.C.N. is a Howard Hughes Medical Institute investigator. M.C.N. and D.R.B. are co-inventors on patents covering the monoclonal antibodies used in the present study.

Author information

Author notes

    • Michel C. Nussenzweig
    •  & Dennis R. Burton

    These authors contributed equally to this work.

Affiliations

  1. Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA

    • Dan H. Barouch
    • , James B. Whitney
    • , Jinyan Liu
    • , Kathryn E. Stephenson
    • , Hui-Wen Chang
    • , Joseph P. Nkolola
    • , Michael S. Seaman
    • , Kaitlin M. Smith
    • , Erica N. Borducchi
    • , Crystal Cabral
    • , Jeffrey Y. Smith
    • , Stephen Blackmore
    • , Srisowmya Sanisetty
    •  & James R. Perry
  2. Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts 02139, USA

    • Dan H. Barouch
    • , Arup K. Chakraborty
    •  & Dennis R. Burton
  3. The Scripps Research Institute, La Jolla, California 92037, USA

    • Brian Moldt
    • , Pascal Poignard
    •  & Dennis R. Burton
  4. The Rockefeller University, New York, New York 10065, USA

    • Florian Klein
    • , Thiago Y. Oliveira
    •  & Michel C. Nussenzweig
  5. Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Karthik Shekhar
    • , Sanjana Gupta
    •  & Arup K. Chakraborty
  6. New England Primate Research Center, Southborough, Massachusetts 01776, USA

    • Matthew Beck
  7. Bioqual, Inc., Rockville, Maryland 20852, USA

    • Mark G. Lewis
  8. Alpha Genesis, Inc., Yemassee, South Carolina 29945, USA

    • William Rinaldi
  9. Howard Hughes Medical Institute, New York, New York 10065, USA

    • Michel C. Nussenzweig

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Contributions

D.H.B., M.C.N. and D.R.B. designed the studies. J.B.W., B.M., F.K., T.Y.O., H.-W.C., S.S. and P.P. led the virological assays. B.M., J.L., K.E.S., M.S.S., K.M.S., E.N.B., C.C., J.Y.S., S.B. and J.R.P. led the immunological assays. K.S., S.G. and A.K.C. led the kinetic analyses. J.B.W., J.P.N., M.B., M.G.L. and W.R. led the monoclonal antibody infusions and clinical care of the rhesus monkeys. D.H.B. led the studies and wrote the paper with all co-authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Dan H. Barouch.

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    Supplementary Data

    This file contains samples used for gp120 Env sequence analysis.

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https://doi.org/10.1038/nature12744

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