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EBioMedicine. 2016 Dec;14:97-111. doi: 10.1016/j.ebiom.2016.11.024. Epub 2016 Nov 21.

Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection.

Author information

1
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
2
Center of Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA, USA.
3
Duke Human Vaccine Institute, Duke School of Medicine, Durham, NC, USA.
4
Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
5
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
6
Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
7
Department of Disease Control, Ministry of Public Health, Nonthaburi, Thailand.
8
Department of Clinical Tropical Medicine, Mahidol University, Bangkok, Thailand.
9
Royal Thai Army Component, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
10
Department of Tropical Hygiene, Mahidol University, Bangkok, Thailand.
11
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA; Department of Laboratory Medicine, University of Washington, Seattle, WA, USA; Department of Global Health, University of Washington, Seattle, WA, USA. Electronic address: jmcelrat@fhcrc.org.

Abstract

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-CSF and HIV-1Bal26 infection. 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.

KEYWORDS:

Antibodies; HIV-1; IgA; IgG; Mucosal immunology; Neutralizing antibodies; Non-human primate rectal challenge model; Vaginal explants

PMID:
27919754
PMCID:
PMC5161443
DOI:
10.1016/j.ebiom.2016.11.024
[Indexed for MEDLINE]
Free PMC Article

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