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Author Notes:

Correspondence: Daniel B. Reeves, dreeves@fredhutch.org

Author contributions: D.B.R., B.T.M., S.T.K., and S.E. conceived the study. D.B.R. and B.T.M. developed the models used in the study. B.T.M. developed the software/code used in the study. D.B.R. and B.T.M. contributed to validation. D.B.R., B.T.M., A.C.dC., Y.H., B.Z., C.A.M., M.J., P.B.G., K.J.B., E.F.C-O, R.R., and P.E. performed analyses. conducted research and/or performed experiments. P.B.G., D.C.M., K.J.B., J.T.S., L.M., N.N.M., C.W., J.I.M., K.E.S., G.D.T., P.A., N.M., J.E.L., M.S.C., L.C., L.N., C.O., P.A.G., M.C., M.E.S., S.T.K., and S.E. provided study materials, laboratory samples, computing resources or other analysis tools. D.B.R., B.T.M., A.C.dC., C.A.M., and P.B.G. curated data. D.B.R. and B.T.M. performed visualization/data presentation. P.B.G., D.C.M., J.T.S., P.E., C.W., J.I.M., G.D.T., M.S.C., L.C., M.E.S., S.T.K., and S.E. supervised effort on this work. P.B.G., G.D.T., M.S.C., and L.C. acquired funding. D.B.R., B.T.M., and L.N.C. wrote the manuscript. All coauthors reviewed and edited the manuscript and provided approval of the final version. These authors contributed equally: Daniel B. Reeves, Bryan T. Mayer. These authors jointly supervised this work: Shelly T. Karuna, Srilatha Edupuganti.

Competing interests: The authors declare no competing interests.

Subjects:

Research Funding:

This work was supported by the National Institutes of Health through award numbers R01 AI150500 (E.F. C-O.), UM1 AI068614 (G.D.T., L.C.), UM1 AI068635 (Y.H., P.B.G.), 4 R37 AI054165-21 (P.B.G.), UM1 AI068618, UM1 AI068619 (M.S.C), UM1 AI068613, UM1 AI068617, P30 AI027757, P30 AI064518, K25 AI155224 (D.B.R.), the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, and the South African Medical Research Council (SAMRC).

Keywords:

  • HIV infections
  • Applied mathematics
  • Scientific data
  • Antibodies

High monoclonal neutralization titers reduced breakthrough HIV-1 viral loads in the Antibody Mediated Prevention trials

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Journal Title:

Nature Communications

Volume:

Volume 14

Publisher:

, Pages 8299-None

Type of Work:

Article | Final Publisher PDF

Abstract:

The Antibody Mediated Prevention (AMP) trials (NCT02716675 and NCT02568215) demonstrated that passive administration of the broadly neutralizing monoclonal antibody VRC01 could prevent some HIV-1 acquisition events. Here, we use mathematical modeling in a post hoc analysis to demonstrate that VRC01 influenced viral loads in AMP participants who acquired HIV. Instantaneous inhibitory potential (IIP), which integrates VRC01 serum concentration and VRC01 sensitivity of acquired viruses in terms of both IC50 and IC80, follows a dose-response relationship with first positive viral load (p = 0.03), which is particularly strong above a threshold of IIP = 1.6 (r = -0.6, p = 2e-4). Mathematical modeling reveals that VRC01 activity predicted from in vitro IC80s and serum VRC01 concentrations overestimates in vivo neutralization by 600-fold (95% CI: 300–1200). The trained model projects that even if future therapeutic HIV trials of combination monoclonal antibodies do not always prevent acquisition, reductions in viremia and reservoir size could be expected.

Copyright information:

© The Author(s) 2023, corrected publication 2024

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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