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Abstract

To protect against human immunodeficiency virus (HIV-1) infection, broadly neutralizing antibodies (bnAbs) must be active at the portals of viral entry in the gastrointestinal or cervicovaginal tracts. The localization and persistence of antibodies at these sites is influenced by the neonatal Fc receptor (FcRn)1,2, whose role in protecting against infection in vivo has not been defined. Here, we show that a bnAb with enhanced FcRn binding has increased gut mucosal tissue localization, which improves protection against lentiviral infection in non-human primates. A bnAb directed to the CD4-binding site of the HIV-1 envelope (Env) protein (denoted VRC01)3 was modified by site-directed mutagenesis to increase its binding affinity for FcRn. This enhanced FcRn-binding mutant bnAb, denoted VRC01-LS, displayed increased transcytosis across human FcRn-expressing cellular monolayers in vitro while retaining FcγRIIIa binding and function, including antibody-dependent cell-mediated cytotoxicity (ADCC) activity, at levels similar to VRC01 (the wild type). VRC01-LS had a threefold longer serum half-life than VRC01 in non-human primates and persisted in the rectal mucosa even when it was no longer detectable in the serum. Notably, VRC01-LS mediated protection superior to that afforded by VRC01 against intrarectal infection with simian–human immunodeficiency virus (SHIV). These findings suggest that modification of FcRn binding provides a mechanism not only to increase serum half-life but also to enhance mucosal localization that confers immune protection. Mutations that enhance FcRn function could therefore increase the potency and durability of passive immunization strategies to prevent HIV-1 infection.

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Acknowledgements

We thank M. Roederer for advice on the design and statistical analysis of animal studies. This research was supported by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), and in part by a grant from the Foundation for the National Institutes of Health with support from the Collaboration for AIDS Vaccine Discovery (CAVD), award OPP1039775, from the Bill & Melinda Gates Foundation. R.S.B. is supported by the NIH (DK044319, DK051362, DK053056 and DK088199) and the Harvard Digestive Diseases Center (DK0034854). T.R. is supported by the German research foundation (DFG; RA 2040/1-1). The findings and conclusions in this report are those of the authors and do not necessarily reflect the views of the funding agencies.

Author information

Author notes

    • Rebecca S. Rudicell
    • , Zhi-yong Yang
    • , Ming Zeng
    • , Scott R. Penzak
    •  & Gary J. Nabel

    Present addresses: Sanofi, 640 Memorial Drive, Cambridge, Massachusetts 02139, USA (R.S.R., Z.-Y.Y. and G.J.N.); Center for Genetics of Host Defense, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235-8505, USA (M.Z.); University of North Texas System College of Pharmacy, 3500 Camp Bowie Boulevard, RES-340J, Fort Worth, Texas 76107, USA (S.R.P.).

Affiliations

  1. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 40, Room 4502, MSC-3005, 40 Convent Drive, Bethesda, Maryland 20892-3005, USA

    • Sung-Youl Ko
    • , Amarendra Pegu
    • , Rebecca S. Rudicell
    • , Zhi-yong Yang
    • , M. Gordon Joyce
    • , Xuejun Chen
    • , Keyun Wang
    • , Saran Bao
    • , Stephen D. Schmidt
    • , John-Paul Todd
    • , Kevin O. Saunders
    • , Srinivas S. Rao
    • , John R. Mascola
    •  & Gary J. Nabel
  2. Division of Gastroenterology, Department of Medicine, Brigham & Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA

    • Thomas D. Kraemer
    • , Timo Rath
    •  & Richard S. Blumberg
  3. Department of Microbiology, Medical School, University of Minnesota, 420 Delaware Street South East, Minneapolis, Minnesota 55455, USA

    • Ming Zeng
    •  & Ashley T. Haase
  4. Clinical Pharmacokinetics Laboratory, Pharmacy Department, Clinical Center, National Institutes of Health, Building 10, 10 Center Drive, Bethesda, Maryland 20814, USA

    • Scott R. Penzak
  5. Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 6700A Rockledge Drive, Room 5235, Bethesda, Maryland 20892, USA

    • Martha C. Nason

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Contributions

S.-Y.K., Z.-Y.Y., J.R.M. and G.J.N. designed the study, analysed the data and prepared the manuscript. A.P. analysed the data, set up the ADCC assay and provided the material for the ADCC assays. R.S.R. and K.O.S. helped to prepare the manuscript. M.G.J. performed the surface plasmon resonance analysis. X.C. performed DNA cloning and protein purification. T.D.K., T.R. and R.S.B. performed the transcytosis assay. S.B., M.Z. and A.T.H. performed immunohistochemical staining. S.D.S. and J.R.M. performed the neutralization assays. K.W., J.-P.T. and S.S.R. performed the pharmacokinetics and challenge study. S.R.P. analysed the pharmacokinetic data. M.C.N. conducted statistical analyses.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to John R. Mascola or Gary J. Nabel.

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DOI

https://doi.org/10.1038/nature13612

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