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Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys

Nature volume 503, pages 224–228 (2013)Cite this article

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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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Figure 1: Therapeutic efficacy of the triple PGT121, 3BNC117 and b12 monoclonal antibody cocktail.
Figure 2: Therapeutic efficacy of the double PGT121 and 3BNC117 monoclonal antibody cocktail.
Figure 3: Therapeutic efficacy of the single monoclonal antibodies PGT121 and 3BNC117.
Figure 4: Therapeutic efficacy of PGT121 or PGT121-containing monoclonal antibody cocktails in chronically SHIV-infected rhesus monkeys.

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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.

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Author notes

  1. Michel C. Nussenzweig and Dennis R. Burton: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02215, Massachusetts, 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, 02139, Massachusetts, USA

    Dan H. Barouch, Arup K. Chakraborty & Dennis R. Burton

  3. The Scripps Research Institute, La Jolla, 92037, California, USA

    Brian Moldt, Pascal Poignard & Dennis R. Burton

  4. The Rockefeller University, New York, 10065, New York, USA

    Florian Klein, Thiago Y. Oliveira & Michel C. Nussenzweig

  5. Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Karthik Shekhar, Sanjana Gupta & Arup K. Chakraborty

  6. New England Primate Research Center, Southborough, 01776, Massachusetts, USA

    Matthew Beck

  7. Bioqual, Inc., Rockville, 20852, Maryland, USA

    Mark G. Lewis

  8. Alpha Genesis, Inc., Yemassee, 29945, South Carolina, USA

    William Rinaldi

  9. Howard Hughes Medical Institute, New York, 10065, New York, USA

    Michel C. Nussenzweig

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  1. Dan H. Barouch
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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.

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Correspondence to Dan H. Barouch.

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Extended data figures and tables

Extended Data Figure 1 Monoclonal antibody titres after administration of the triple PGT121, 3BNC117 and b12 monoclonal antibody cocktail.

PGT121, 3BNC117 and b12 titres in the monkeys described in Fig. 1 after infusion of the triple monoclonal antibody cocktail (arrows).

Extended Data Figure 2 Neutralizing antibody titres after administration of the triple PGT121, 3BNC117 and b12 monoclonal antibody cocktail.

SHIV-SF162P3 and SHIV-SF162P4 serum neutralizing antibody ID50 titres in the monkeys described in Fig. 1 after infusion of the triple monoclonal antibody cocktail (left) or saline or DEN3 (right).

Extended Data Figure 3 Gag-specific T lymphocyte responses after administration of the triple PGT121, 3BNC117 and b12 monoclonal antibody cocktail.

Gag-specific IFN-γ+ CD8+ (left) and CD4+ (right) T-lymphocyte responses by multiparameter intracellular cytokine staining assays in the monkeys described in Fig. 1 after infusion of the triple monoclonal antibody cocktail.

Extended Data Figure 4 Monoclonal antibody titres after administration of the double PGT121 and 3BNC117 monoclonal antibody cocktail.

a–c, PGT121, 3BNC117 and b12 titres in the monkeys described in Fig. 2 that received PGT121, 3BCN117 and b12 (a); PGT121 and 3BNC117 (b); or the second infusion of PGT121 and 3BNC117 (c).

Extended Data Figure 5 Monkey anti-human antibody titres after monoclonal antibody administration.

ELISAs assessing anti-b12, anti-PGT121, anti-3BNC117 and anti-DEN3 antibodies at week 6 and week 10 after monoclonal antibody infusion in the monkeys described in Fig. 2.

Extended Data Figure 6 Neutralization sensitivity of SHIV-SF162P3 pseudovirus and our SHIV-SF162P3 challenge stock.

TZM-bl neutralization assays of PGT121, 3BNC117 and b12 against the SHIV-SF162P3 pseudovirus (top) and against the SHIV-SF162P3 challenge stock (middle, bottom). Note sensitivity of our SHIV-SF162P3 challenge stock to PGT121 but relative resistance to 3BNC117.

Extended Data Figure 7 Monoclonal antibody titres after administration of the single monoclonal antibodies PGT121 and 3BNC117.

PGT121 and 3BNC117 titres in the monkeys described in Fig. 3 after infusion of the single monoclonal antibodies.

Extended Data Figure 8 Virus replicative capacity at baseline and following virus rebound.

Numbers of GFP-positive infected GHOST indicator cells per well after 3 and 6 days of culture with baseline or rebound SHIV-SF162P3 virus.

Extended Data Figure 9 Monoclonal antibody sensitivity to N332A mutated SHIV-SF162P3.

TZM-bl neutralization assays of PGT121, PGT124, PGT128, PGT130 and PGV04 against SHIV-SF162P3 containing the N332A mutation. Note 100-fold reduced sensitivity to PGT121 but more profound escape from PGT124 and PGT128.

Extended Data Table 1 Viral decay kinetics
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Barouch, D., Whitney, J., Moldt, B. et al. Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature 503, 224–228 (2013). https://doi.org/10.1038/nature12744

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