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Title: Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection
Authors: Rena D. Astronomo
Sampa Santra
Lamar Ballweber-Fleming
Katharine G. Westerberg
Linh Mach
Tiffany Hensley-McBain
Laura Sutherland
Benjamin Mildenberg
Georgeanna Morton
Nicole L. Yates
Gregory J. Mize
Justin Pollara
Florian Hladik
Christina Ochsenbauer
Thomas N. Denny
Ranjit Warrier
Supachai Rerks-Ngarm
Punnee Pitisuttithum
Sorachai Nitayapan
Jaranit Kaewkungwal
Guido Ferrari
George M. Shaw
Shi Mao Xia
Hua Xin Liao
David C. Montefiori
Georgia D. Tomaras
Barton F. Haynes
M. Juliana McElrath
Fred Hutchinson Cancer Research Center
Beth Israel Deaconess Medical Center
Duke University
University of Washington, Seattle
University of Alabama at Birmingham
University of Pennsylvania
Thailand Ministry of Public Health
Mahidol University
Armed Forces Research Institute of Medical Sciences, Thailand
Keywords: Biochemistry, Genetics and Molecular Biology
Issue Date: 1-Dec-2016
Citation: EBioMedicine. Vol.14, (2016), 97-111
Abstract: © 2016 The Authors HIV-1 infection occurs primarily through mucosal transmission. Application of biologically relevant mucosal models can advance understanding of the functional properties of antibodies that mediate HIV protection, thereby guiding antibody-based vaccine development. Here, we employed a human ex vivo vaginal HIV-1 infection model and a rhesus macaque in vivo intrarectal SHIV challenge model to probe the protective capacity of monoclonal broadly-neutralizing (bnAb) and non-neutralizing Abs (nnAbs) that were functionally modified by isotype switching. For human vaginal explants, we developed a replication-competent, secreted NanoLuc reporter virus system and showed that CD4 binding site bnAbs b12 IgG1 and CH31 IgG1 and IgA2 isoforms potently blocked HIV-1JR-CSFand HIV-1Bal26infection. However, IgG1 and IgA nnAbs, either alone or together, did not inhibit infection despite the presence of FcR-expressing effector cells in the tissue. In macaques, the CH31 IgG1 and IgA2 isoforms infused before high-dose SHIV challenge were completely to partially protective, respectively, while nnAbs (CH54 IgG1 and CH38 mIgA2) were non-protective. Importantly, in both mucosal models IgG1 isotype bnAbs were more protective than the IgA2 isotypes, attributable in part to greater neutralization activity of the IgG1 variants. These findings underscore the importance of potent bnAb induction as a primary goal of HIV-1 vaccine development.
ISSN: 23523964
Appears in Collections:Scopus 2016-2017

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