Enhanced neonatal Fc receptor function improves protection against primate SHIV infection

Sung Youl Ko, Amarendra Pegu, Rebecca S. Rudicell, Zhi Yong Yang, M. Gordon Joyce, Xuejun Chen, Keyun Wang, Saran Bao, Thomas D. Kraemer, Timo Rath, Ming Zeng, Stephen D. Schmidt, John Paul Todd, Scott R. Penzak, Kevin O. Saunders, Martha C. Nason, Ashley T. Haase, Srinivas S. Rao, Richard S. Blumberg, John R. Mascola & 1 others Gary J. Nabel

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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), 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) 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.

Original languageEnglish (US)
Pages (from-to)642-645
Number of pages4
JournalNature
Volume514
Issue number7524
DOIs
StatePublished - Aug 13 2014

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Simian Immunodeficiency Virus
Virus Diseases
Primates
HIV-1
HIV
HIV Infections
Half-Life
Mucous Membrane
Infection
Serum
Antibody-Dependent Cell Cytotoxicity
Transcytosis
Passive Immunization
Site-Directed Mutagenesis
Neutralizing Antibodies
Binding Sites
Mutation
neonatal Fc receptors
Antibodies
Proteins

Cite this

Ko, S. Y., Pegu, A., Rudicell, R. S., Yang, Z. Y., Joyce, M. G., Chen, X., ... Nabel, G. J. (2014). Enhanced neonatal Fc receptor function improves protection against primate SHIV infection. Nature, 514(7524), 642-645. https://doi.org/10.1038/nature13612

Enhanced neonatal Fc receptor function improves protection against primate SHIV infection. / Ko, Sung Youl; Pegu, Amarendra; Rudicell, Rebecca S.; Yang, Zhi Yong; Joyce, M. Gordon; Chen, Xuejun; Wang, Keyun; Bao, Saran; Kraemer, Thomas D.; Rath, Timo; Zeng, Ming; Schmidt, Stephen D.; Todd, John Paul; Penzak, Scott R.; Saunders, Kevin O.; Nason, Martha C.; Haase, Ashley T.; Rao, Srinivas S.; Blumberg, Richard S.; Mascola, John R.; Nabel, Gary J.

In: Nature, Vol. 514, No. 7524, 13.08.2014, p. 642-645.

Research output: Contribution to journalArticle

Ko, SY, Pegu, A, Rudicell, RS, Yang, ZY, Joyce, MG, Chen, X, Wang, K, Bao, S, Kraemer, TD, Rath, T, Zeng, M, Schmidt, SD, Todd, JP, Penzak, SR, Saunders, KO, Nason, MC, Haase, AT, Rao, SS, Blumberg, RS, Mascola, JR & Nabel, GJ 2014, 'Enhanced neonatal Fc receptor function improves protection against primate SHIV infection', Nature, vol. 514, no. 7524, pp. 642-645. https://doi.org/10.1038/nature13612
Ko SY, Pegu A, Rudicell RS, Yang ZY, Joyce MG, Chen X et al. Enhanced neonatal Fc receptor function improves protection against primate SHIV infection. Nature. 2014 Aug 13;514(7524):642-645. https://doi.org/10.1038/nature13612
Ko, Sung Youl ; Pegu, Amarendra ; Rudicell, Rebecca S. ; Yang, Zhi Yong ; Joyce, M. Gordon ; Chen, Xuejun ; Wang, Keyun ; Bao, Saran ; Kraemer, Thomas D. ; Rath, Timo ; Zeng, Ming ; Schmidt, Stephen D. ; Todd, John Paul ; Penzak, Scott R. ; Saunders, Kevin O. ; Nason, Martha C. ; Haase, Ashley T. ; Rao, Srinivas S. ; Blumberg, Richard S. ; Mascola, John R. ; Nabel, Gary J. / Enhanced neonatal Fc receptor function improves protection against primate SHIV infection. In: Nature. 2014 ; Vol. 514, No. 7524. pp. 642-645.
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