title: Defense-in-depth by mucosally administered anti-HIV dimeric IgA2 and systemic IgG1 mAbs: complete protection of rhesus monkeys from mucosal SHIV challenge.
abstract: Although IgA is the most abundantly produced immunoglobulin in humans, its role in preventing HIV-1 acquisition, which occurs mostly via mucosal routes, remains unclear. In our passive mucosal immunizations of rhesus macaques (RMs), the anti-HIV-1 neutralizing monoclonal antibody (nmAb) HGN194, given either as dimeric IgA1 (dIgA1) or dIgA2 intrarectally (i.r.), protected 83% or 17% of the RMs against i.r. simian-human immunodeficiency virus (SHIV) challenge, respectively. Data from the RV144 trial implied that vaccine-induced plasma IgA counteracted the protective effector mechanisms of IgG1 with the same epitope specificity. We thus hypothesized that mucosal dIgA2 might diminish the protection provided by IgG1 mAbs targeting the same epitope. To test our hypothesis, we administered HGN194 IgG1 intravenously (i.v.) either alone or combined with i.r. HGN194 dIgA2. We enrolled SHIV-exposed, persistently aviremic RMs protected by previously administered nmAbs; RM anti-human IgG responses were undetectable. However, low-level SIV Gag-specific proliferative T-cell responses were found. These animals resemble HIV-exposed, uninfected humans, in which local and systemic cellular immune responses have been observed. HGN194 IgG1 and dIgA2 used alone and the combination of the two neutralized the challenge virus equally well in vitro. All RMs given only i.v. HGN194 IgG1 became infected. In contrast, all RMs given HGN194 IgG1+dIgA2 were completely protected against high-dose i.r. SHIV-1157ipEL-p challenge. These data imply that combining suboptimal defenses at the mucosal and systemic levels can completely prevent virus acquisition. Consequently, active vaccination should focus on defense-in-depth, a strategy that seeks to build up defensive fall-back positions well behind the fortified frontline.
authors.affiliation: Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX, USA; Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
authors.forename: Anton M
authors.initials: AM
authors.lastname: Sholukh
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Watkins
authors.affiliation: Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX, USA; Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Vyas
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California, Irvine School of Medicine, Irvine, CA, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX, USA; Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
authors.forename: Samir K
authors.initials: SK
authors.lastname: Lakhashe
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
authors.forename: Swati
authors.initials: S
authors.lastname: Thorat
authors.affiliation: Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX, USA.
authors.forename: Mingkui
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Girish
authors.initials: G
authors.lastname: Hemashettar
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Bachler
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California, Irvine School of Medicine, Irvine, CA, USA.
authors.forename: Donald N
authors.initials: DN
authors.lastname: Forthal
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA; Yerkes National Primate Research Center, Atlanta, GA, USA.
authors.forename: Francois
authors.initials: F
authors.lastname: Villinger
authors.affiliation: The Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
authors.forename: Quentin J
authors.initials: QJ
authors.lastname: Sattentau
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6BT, UK.
authors.forename: Robin A
authors.initials: RA
authors.lastname: Weiss
authors.affiliation: Humabs BioMed SA, Bellinzona 6500, Switzerland.
authors.forename: Gloria
authors.initials: G
authors.lastname: Agatic
authors.affiliation: Humabs BioMed SA, Bellinzona 6500, Switzerland; Institute for Research in Biomedicine, Bellinzona 6500, Switzerland.
authors.forename: Davide
authors.initials: D
authors.lastname: Corti
authors.affiliation: Institute for Research in Biomedicine, Bellinzona 6500, Switzerland; Eidgenoessische Technische Hochschule, Zurich CH-8093, Switzerland.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lanzavecchia
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Heeney
authors.affiliation: Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX, USA; Southwest National Primate Research Center, San Antonio, TX, USA; Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: rruprecht@txbiomed.org.
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Ruprecht
mesh_terms: D061605:Administration, Intravenous; D058956:Administration, Mucosal; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D015483:HIV Antibodies / Q000008:administration & dosage* / Q000097:blood; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D018928:Immunity, Mucosal; D007116:Immunization, Passive; D007070:Immunoglobulin A / Q000008:administration & dosage / Q000097:blood / Q000276:immunology; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000097:blood / Q000276:immunology; D008253:Macaca mulatta; D009092:Mucous Membrane / Q000276:immunology; D012367:RNA, Viral / Q000097:blood; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control*; D015302:Simian Immunodeficiency Virus / Q000276:immunology* / Q000472:pathogenicity; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D012367:RNA, Viral
keywords: (6 max); Complete protection; IgA; IgG; Passive immunization; Rhesus monkey; SHIV-C mucosal challenge