Defense-in-depth by mucosally administered anti-HIV dimeric IgA2 and systemic IgG1 mAbs: Complete protection of rhesus monkeys from mucosal SHIV challenge

Autor: Robin A. Weiss, Donald N. Forthal, Jennifer D. Watkins, Antonio Lanzavecchia, Ruth M. Ruprecht, Samir K. Lakhashe, Barbara C. Bachler, Mingkui Zhou, Girish Hemashettar, Francois Villinger, Anton M Sholukh, Sandeep Gupta, Davide Corti, Swati Thorat, Quentin J. Sattentau, Gloria Agatic, Jonathan L. Heeney, Hemant K. Vyas
Přispěvatelé: Heeney, Jonathan [0000-0003-2702-1621], Apollo - University of Cambridge Repository
Rok vydání: 2015
Předmět:
T-Lymphocytes
Simian Acquired Immunodeficiency Syndrome
(6 max)
HIV Antibodies
Passive
Medical and Health Sciences
Epitope
Monoclonal
Administration
Mucosal
Viral
SHIV-C mucosal challenge
Neutralizing
Immunity
Cellular
Mucosal
Effector
Simian immunodeficiency virus
Antibodies
Monoclonal
Biological Sciences
Vaccination
Infectious Diseases
Administration
RNA
Viral
HIV/AIDS
Molecular Medicine
Administration
Intravenous
Simian Immunodeficiency Virus
Antibody
Intravenous
Infection
IgA
Pediatric Research Initiative
IgG
medicine.drug_class
Biology
Monoclonal antibody
Article
Antibodies
Virus
Vaccine Related
Immune system
Virology
Immunology and Microbiology(all)
medicine
Animals
Humans
Complete protection
Vaccine Related (AIDS)
Immunity
Mucosal
Mucous Membrane
Agricultural and Veterinary Sciences
General Veterinary
General Immunology and Microbiology
Prevention
Passive immunization
Immunization
Passive
Immunity
Public Health
Environmental and Occupational Health
Antibodies
Neutralizing
Macaca mulatta
veterinary(all)
In vitro
Immunoglobulin A
Good Health and Well Being
Immunoglobulin G
Immunology
HIV-1
Rhesus monkey
biology.protein
RNA
Immunization
Cellular
Zdroj: Vaccine, vol 33, iss 17
ISSN: 0264-410X
Popis: 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.
Databáze: OpenAIRE
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