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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  1. 1.

    & FcRn: the neonatal Fc receptor comes of age. Nature Rev. Immunol. 7, 715–725 (2007)

  2. 2.

    & Multitasking by exploitation of intracellular transport functions: the many faces of FcRn. Adv. Immunol. 103, 77–115 (2009)

  3. 3.

    et al. Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science 329, 856–861 (2010)

  4. 4.

    et al. Fc receptor but not complement binding is important in antibody protection against HIV. Nature 449, 101–104 (2007)

  5. 5.

    & Fcγ receptors as regulators of immune responses. Nature Rev. Immunol. 8, 34–47 (2008)

  6. 6.

    et al. Broadly neutralizing human anti-HIV antibody 2G12 is effective in protection against mucosal SHIV challenge even at low serum neutralizing titers. PLoS Pathogens 5, e1000433 (2009)

  7. 7.

    et al. Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science 326, 285–289 (2009)

  8. 8.

    et al. Broadly neutralizing monoclonal antibodies 2F5 and 4E10 directed against the human immunodeficiency virus type 1 gp41 membrane-proximal external region protect against mucosal challenge by simian–human immunodeficiency virus SHIVBa-L. J. Virol. 84, 1302–1313 (2010)

  9. 9.

    et al. Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 477, 466–470 (2011)

  10. 10.

    et al. Broad and potent neutralization of HIV-1 by a gp41-specific human antibody. Nature 491, 406–412 (2012)

  11. 11.

    et al. Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo. Proc. Natl Acad. Sci. USA 109, 18921–18925 (2012)

  12. 12.

    et al. Pulmonary delivery of an erythropoietin Fc fusion protein in non-human primates through an immunoglobulin transport pathway. Proc. Natl Acad. Sci. USA 101, 9763–9768 (2004)

  13. 13.

    , & Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn). J. Biol. Chem. 281, 23514–23524 (2006)

  14. 14.

    et al. An engineered human IgG1 antibody with longer serum half-life. J. Immunol. 176, 346–356 (2006)

  15. 15.

    et al. Enhanced half-life of genetically engineered human IgG1 antibodies in a humanized FcRn mouse model: potential application in humorally mediated autoimmune disease. Int. Immunol. 18, 1759–1769 (2006)

  16. 16.

    et al. Enhanced antibody half-life improves in vivo activity. Nature Biotechnol. 28, 157–159 (2010)

  17. 17.

    et al. Increasing the affinity of a human IgG1 for the neonatal Fc receptor: biological consequences. J. Immunol. 169, 5171–5180 (2002)

  18. 18.

    et al. The MHC class I-like IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG–Fc-coupled drugs. J. Immunol. 170, 3528–3533 (2003)

  19. 19.

    et al. Antibody-dependent cellular cytotoxicity against primary HIV-infected CD4+ T cells is directly associated with the magnitude of surface IgG binding. J. Virol. 86, 8672–8680 (2012)

  20. 20.

    et al. A simplified method for the rapid fluorometric assessment of antibody-dependent cell-mediated cytotoxicity. J. Immunol. Methods 308, 53–67 (2006)

  21. 21.

    et al. Neutralizing IgG at the portal of infection mediates protection against vaginal simian/human immunodeficiency virus challenge. J. Virol. 87, 11604–11616 (2013)

  22. 22.

    , & Broadly neutralizing antibodies and the search for an HIV-1 vaccine: the end of the beginning. Nature Rev. Immunol. 13, 693–701 (2013)

  23. 23.

    et al. Mucosal immunity induced by enhance-potency inactivated and oral polio vaccines. J. Infect. Dis. 163, 1–6 (1991)

  24. 24.

    et al. Poliovirus type 1 enters the human host through intestinal M cells. Gastroenterology 98, 56–58 (1990)

  25. 25.

    et al. Human neonatal Fc receptor mediates transport of IgG into luminal secretions for delivery of antigens to mucosal dendritic cells. Immunity 20, 769–783 (2004)

  26. 26.

    et al. Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc. Natl Acad. Sci. USA 105, 7552–7557 (2008)

  27. 27.

    et al. Transfer of IgG in the female genital tract by MHC class I-related neonatal Fc receptor (FcRn) confers protective immunity to vaginal infection. Proc. Natl Acad. Sci. USA 108, 4388–4393 (2011)

  28. 28.

    et al. A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrob. Agents Chemother. 57, 6147–6153 (2013)

  29. 29.

    et al. Neutralizing antibodies to HIV-1 envelope protect more effectively in vivo than those to the CD4 receptor. Sci. Transl. Med. 6, 243ra88 (2014)

  30. 30.

    et al. The covalent structure of an entire γG immunoglobulin molecule. Proc. Natl Acad. Sci. USA 63, 78–85 (1969)

  31. 31.

    , & Expression and crystallization of a soluble and functional form of an Fc receptor related to class I histocompatibility molecules. Proc. Natl Acad. Sci. USA 89, 638–642 (1992)

  32. 32.

    et al. Human immunodeficiency virus type 1 env clones from acute and early subtype B infections for standardized assessments of vaccine-elicited neutralizing antibodies. J. Virol. 79, 10108–10125 (2005)

  33. 33.

    et al. Efficient protein boosting after plasmid DNA or recombinant adenovirus immunization with HIV-1 vaccine constructs. Vaccine 25, 1398–1408 (2007)

  34. 34.

    et al. Tiered categorization of a diverse panel of HIV-1 Env pseudoviruses for assessment of neutralizing antibodies. J. Virol. 84, 1439–1452 (2010)

  35. 35.

    , , , & Functional reconstitution of human FcRn in Madin–Darby canine kidney cells requires co-expressed human β2-microglobulin. J. Biol. Chem. 277, 28038–28050 (2002)

  36. 36.

    et al. Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV infections. J. Clin. Invest. 121, 998–1008 (2011)

  37. 37.

    et al. Neonatal Fc receptor expression in dendritic cells mediates protective immunity against colorectal cancer. Immunity 39, 1095–1107 (2013)

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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.).


  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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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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