Abstract

Interruption of combination antiretroviral therapy (ART) in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117, a broad and potent neutralizing antibody (bNAb) against the CD4 binding site of HIV-1 Env1, in the setting of analytical treatment interruption (ATI) in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Two or four 30 mg/kg infusions of 3BNC117, separated by 3 or 2 weeks, respectively, were generally well tolerated. The infusions were associated with a delay in viral rebound for 5-9 weeks after 2 infusions, and up to 19 weeks after 4 infusions, or an average of 6.7 and 9.9 weeks respectively, compared with 2.6 weeks for historical controls (p=<1e-5). Rebound viruses arose predominantly from a single provirus. In most individuals, emerging viruses showed increased resistance indicating escape. However, 30% of participants remained suppressed until antibody concentrations waned below 20 μg/ml, and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9-19 weeks. We conclude that administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during ATI in humans.

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Acknowledgements

We would like to thank the trial participants for their invaluable support; We thank the Rockefeller University Hospital Clinical Research Support Office and nursing staff for help with recruitment and study implementation, especially Noreen Buckley, Arlene Hurley, Sivan Ben Avraham Shulman and Lauren Corregano. All members of the Nussenzweig lab, especially Till Schoofs, Ari Halper-Stromberg, Mila and Zoran Jankovic. Cecille Unson-O'Brien, Juan Dizon, Renise Baptiste and Rebeka Levin for sample processing and study coordination; Audrey Louie for regulatory support; Pat Fast and Harriet Park for clinical monitoring. Elena Giorgi and William Fischer from Los Alamos National Laboratory. Rajesh Tim Gandhi, Jonathan Li and The AIDS Clinical Trials Group (grant UM1 AI068636) and its Statistical and Data Management Center (grant UM1 AI068634). This study was supported by the following grants: Collaboration for AIDS Vaccine Discovery grant OPP1033115 (M.C.N.) and OPP1032144 (M.S.S.). Grant 8 UL1 TR000043 from the National Center for Advancing Translational Sciences (NCATS); NIH Clinical and Translational Science Award (CTSA) program; NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) 1UM1 AI100663-01 (M.C.N) and 5UM1 AI100645-03 (B.H.H.); Bill and Melinda Gates Foundation grants OPP1092074 and OPP1124068 (M.C.N); NIH HIVRAD P01 AI100148 (PJB and MCN); the Robertson Foundation to M.C.N. M.C.N. is a Howard Hughes Medical Institute Investigator. Ruth L. Kirschstein National Research Service Award. F30 AI112426 (E.F.K); F31 AI118555 (J.A.H.); The NIH Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) 1UM1 AI00645 (B.H.H.); The University of Pennsylvania Center for AIDS Research (CFAR) Single Genome Amplification Service Center P30 AI045008 (B.H.H.); The NIH Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID and 1UM1-AI100663) (B.D.W).

Author information

Author notes

    • Johannes F. Scheid
    •  & Joshua A. Horwitz

    These authors contributed equally to this work.

Affiliations

  1. Laboratory of Molecular Immunology, and 14Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065

    • Johannes F. Scheid
    • , Joshua A. Horwitz
    • , Yotam Bar-On
    • , Ching-Lan Lu
    • , Julio C. C. Lorenzi
    • , Malte Braunschweig
    • , Lilian Nogueira
    • , Thiago Oliveira
    • , Irina Shimeliovich
    • , Roshni Patel
    • , Yehuda Z. Cohen
    • , Sonya Hadrigan
    • , Allison Settler
    • , Maggi Witmer-Pack
    • , Florian Klein
    • , Sarah J. Schlesinger
    • , Michel C. Nussenzweig
    •  & Marina Caskey
  2. Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114

    • Johannes F. Scheid
  3. Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104

    • Edward F. Kreider
    • , Gerald H. Learn
    •  & Beatrice H. Hahn
  4. Department of Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, Campus E1 4, 66123 Saarbrücken, Germany

    • Anna Feldmann
    •  & Nico Pfeifer
  5. Division of Infectious Diseases, Weill Medical College of Cornell University, New York, NY 10065, USA

    • Leah Burke
    •  & Roy M. Gulick
  6. Division of Biology, California Institute of Technology, Pasadena, California 91125

    • Anthony P. West, Jr.
    •  & Pamela J. Bjorkman
  7. Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA

    • Boris Juelg
    •  & Bruce D. Walker
  8. Celldex Therapeutics, Inc., Hampton, NJ 08827, USA

    • Tibor Keler
    •  & Thomas Hawthorne
  9. Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10467

    • Barry Zingman
  10. Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215

    • Michael S. Seaman
  11. Laboratory of Experimental Immunology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany

    • Florian Klein
  12. Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, 50937 Cologne, Germany

    • Florian Klein
  13. Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114

    • Bruce D. Walker
    •  & Michel C. Nussenzweig

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Contributions

M.C.N, J.F.S, J.A.H and M.C wrote the manuscript; J.F.S, M.C and M.C.N designed the trial; J.F.S, J.A.H, Y.B, J.C.C.L, L.N, Y.Z.C, C-L.L and M.B performed tissue culture experiments and SGS amplifications; M.S.S performed TZM-bl assays; J.F.S, J.A.H, Y.B, E.F.K, T.O, A.P.W, G.H.L, P.J.B, F.K, S.J.S, B.H.H, M.C.N and M.C analyzed the data; E.F.K, G.H.L and B.H.H performed SGA analysis; I.S, R.P and J.F.S processed patient samples; L.B, S.H, A.S, M.W-P, B.Z, R.M.G, S.J.S and M.C performed patient recruitment; A.F and N.P performed statistical analyses; B.J and B.D.W performed antigen specific T cell experiments; T.K and T.H produced 3BNC117 and provided PK data.

Competing interests

There are pending patent applications on the 3BNC117 and 10-1074 antibodies by Rockefeller University on which M.C.N. and J.F.S. are inventors. The patents are not licensed by any companies. Neither M.C.N. nor J.F.S. have any competing financial interests.

Corresponding authors

Correspondence to Michel C. Nussenzweig or Marina Caskey.

There are pending patent applications on the 3BNC117 and 10-1074 antibodies by Rockefeller University on which M.C.N and J.F.S are inventors. The patents are not licensed by any companies.

Reviewer Information Nature thanks S. Deeks, D. Richman and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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    This file contains supplementary Figures 1-2, Supplementary Tables 1-9 and Supplementary References. This file was updated on 27 July 2016 to correct the reference list.

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https://doi.org/10.1038/nature18929

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