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doi: 10.1097/QAD.0b013e328360eac6
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Anti-HIV IgA isotypes: differential virion capture and inhibition of transcytosis are linked to prevention of mucosal R5 SHIV transmission

Watkins, Jennifer D.a,b; Sholukh, Anton M.a,b; Mukhtar, Muhammad M.a,b; Siddappa, Nagadenahalli B.a,b,*; Lakhashe, Samir K.a,b; Kim, Mikyunga,b; Reinherz, Ellis L.a,b; Gupta, Sandeepc; Forthal, Donald N.c; Sattentau, Quentin J.d; Villinger, Francoise,f; Corti, Davideg; Ruprecht, Ruth M.a,b; for the CAVD Project Group

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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.

© 2013 Lippincott Williams & Wilkins, Inc.


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