title: Enhanced neonatal Fc receptor function improves protection against primate SHIV infection.
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.
authors.affiliation: 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.
authors.forename: Sung-Youl
authors.initials: SY
authors.lastname: Ko
authors.affiliation: 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.
authors.forename: Amarendra
authors.initials: A
authors.lastname: Pegu
authors.affiliation: 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 [2] 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.).
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Rudicell
authors.affiliation: 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 [2] 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.).
authors.forename: Zhi-yong
authors.initials: ZY
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: M Gordon
authors.initials: MG
authors.lastname: Joyce
authors.affiliation: 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.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Keyun
authors.initials: K
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Saran
authors.initials: S
authors.lastname: Bao
authors.affiliation: Division of Gastroenterology, Department of Medicine, Brigham &Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Kraemer
authors.affiliation: Division of Gastroenterology, Department of Medicine, Brigham &Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.
authors.forename: Timo
authors.initials: T
authors.lastname: Rath
authors.affiliation: 1] Department of Microbiology, Medical School, University of Minnesota, 420 Delaware Street South East, Minneapolis, Minnesota 55455, USA [2] 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.).
authors.forename: Ming
authors.initials: M
authors.lastname: Zeng
authors.affiliation: 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.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Schmidt
authors.affiliation: 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.
authors.forename: John-Paul
authors.initials: JP
authors.lastname: Todd
authors.affiliation: 1] Clinical Pharmacokinetics Laboratory, Pharmacy Department, Clinical Center, National Institutes of Health, Building 10, 10 Center Drive, Bethesda, Maryland 20814, USA [2] 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.).
authors.forename: Scott R
authors.initials: SR
authors.lastname: Penzak
authors.affiliation: 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.
authors.forename: Kevin O
authors.initials: KO
authors.lastname: Saunders
authors.affiliation: 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.
authors.forename: Martha C
authors.initials: MC
authors.lastname: Nason
authors.affiliation: Department of Microbiology, Medical School, University of Minnesota, 420 Delaware Street South East, Minneapolis, Minnesota 55455, USA.
authors.forename: Ashley T
authors.initials: AT
authors.lastname: Haase
authors.affiliation: 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.
authors.forename: Srinivas S
authors.initials: SS
authors.lastname: Rao
authors.affiliation: Division of Gastroenterology, Department of Medicine, Brigham &Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
authors.affiliation: 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.
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.affiliation: 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 [2] 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.).
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Nabel
mesh_terms: D000285:Administration, Rectal; D000818:Animals; D057134:Antibodies, Neutralizing / Q000032:analysis / Q000097:blood / Q000235:genetics / Q000276:immunology*; D000914:Antibodies, Viral / Q000032:analysis / Q000097:blood / Q000235:genetics / Q000276:immunology*; D000915:Antibody Affinity / Q000235:genetics / Q000276:immunology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D001665:Binding Sites / Q000235:genetics; D015704:CD4 Antigens / Q000378:metabolism; D005260:Female; D006678:HIV / Q000737:chemistry / Q000276:immunology; D015483:HIV Antibodies / Q000032:analysis / Q000097:blood / Q000235:genetics / Q000276:immunology; D019302:HIV Envelope Protein gp160 / Q000737:chemistry / Q000276:immunology; D015658:HIV Infections / Q000276:immunology* / Q000517:prevention & control*; D006207:Half-Life; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D018928:Immunity, Mucosal / Q000276:immunology; D007116:Immunization, Passive; D007413:Intestinal Mucosa / Q000276:immunology; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D016297:Mutagenesis, Site-Directed; D011961:Receptors, Fc / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism; D012007:Rectum / Q000276:immunology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000517:prevention & control*; D015302:Simian Immunodeficiency Virus / Q000276:immunology; D057900:Transcytosis
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D015704:CD4 Antigens; C496124:FCGR3A protein, human; D015483:HIV Antibodies; D019302:HIV Envelope Protein gp160; D015395:Histocompatibility Antigens Class I; D011961:Receptors, Fc; D017452:Receptors, IgG; C100688:Fc receptor, neonatal