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

Item Type:	Article
Title:	Defense-in-depth by mucosally administered anti-HIV dimeric IgA2 and systemic IgG1 mAbs: Complete protection of rhesus monkeys from mucosal SHIV challenge
Creators Name:	Sholukh, A.M. and Watkins, J.D. and Vyas, H.K. and Gupta, S. and Lakhashe, S.K. and Thorat, S. and Zhou, M. and Hemashettar, G. and Bachler, B.C. and Forthal, D.N. and Villinger, F. and Sattentau, Q.J. and Weiss, R.A. and Agatic, G. and Corti, D. and Lanzavecchia, A. and Heeney, J.L. and Ruprecht, R.M.
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.
Keywords:	IgA, IgG, Complete Protection, Passive Immunization, Rhesus Monkey, SHIV-C Mucosal Challenge, (6 Max), Animals, Macaca Mulatta
Source:	Vaccine
ISSN:	0264-410X
Publisher:	Elsevier
Volume:	33
Number:	17
Page Range:	2086-95
Date:	21 April 2015
Additional Information:	Copyright © 2015 Elsevier Ltd. All rights reserved.
Official Publication:	https://doi.org/10.1016/j.vaccine.2015.02.020
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

Repository Staff Only: item control page