Anti-HIV IgA isotypes: differential virion capture and inhibition of transcytosis are linked to prevention of mucosal R5 SHIV transmission

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Item Type:	Article
Title:	Anti-HIV IgA isotypes: differential virion capture and inhibition of transcytosis are linked to prevention of mucosal R5 SHIV transmission
Creators Name:	Watkins, J.D., Sholukh, A.M., Mukhtar, M.M., Siddappa, N.B., Lakhashe, S.K., Kim, M., Reinherz, E.L., Gupta, S., Forthal, Do.N., Sattentau, Q.J., Villinger, F., Corti, D. and Ruprecht, R.M.
Abstract:	OBJECTIVE: Although passive immunization with anti-HIV-1 Env IgG1 neutralizing monoclonal antibodies (nmAbs) prevented simian-human immunodeficiency virus (SHIV) infection in rhesus monkeys, IgA nmAbs have not been tested. Here, we sought to determine whether human anti-HIV-1 dimeric (d)IgA1, dIgA2, and IgG1 differ in their ability to prevent mucosal R5 SHIV acquisition in rhesus monkeys. DESIGN: DIgA1, dIgA2, and IgG1 versions of nmAb HGN194 were applied intrarectally in three rhesus monkey groups 30 min before intrarectal SHIV challenge. METHODS: After a control pharmacokinetic study confirmed that nmAb concentrations in rectal fluids over time were similar for all HGN194 isotypes, control and nmAb-treated animals were challenged intrarectally with an R5 SHIV, and viral loads were monitored. RESULTS: Unexpectedly, dIgA1 provided the best protection in vivo--although all nmAbs showed similar neutralizing activity in vitro. Five out of the six dIgA1-treated rhesus monkeys remained virus-free compared to only one out of six animals given dIgA2 (P=0.045 by log-rank test) and two out of six rhesus monkeys treated with IgG1 forms of the nmAb (P=0.12). Protection correlated significantly with virion capture activity by a given nmAb form, as well as inhibition of transcytosis of cell-free virus across an epithelial cell layer in vitro. CONCLUSIONS: Our data imply that dIgA1-mediated capturing of virions in mucosal secretions and inhibition of transcytosis can provide significant prevention of lentiviral acquisition--over and above direct virus neutralization. Vaccine strategies that induce mucosal IgA, especially IgA1, should be developed as a first line of defense against HIV-1, a virus predominantly transmitted mucosally.
Keywords:	HIV Neutralization, Immunoglobulin A Isotypes, Mucosal Transmission, R5 SHIV, Transcytosis, Virion Capture, Animals, Macaca Mulatta
Source:	AIDS
ISSN:	0269-9370
Publisher:	Lippincott Williams & Wilkins
Volume:	27
Number:	9
Page Range:	F13-F20
Date:	1 June 2013
Official Publication:	https://doi.org/10.1097/QAD.0b013e328360eac6
PubMed:	View item in PubMed

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