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

• Type of Material: Article
• Authors: Jennifer D. Watkins, Dana Farber Cancer Institute; Anton M. Sholukh, Dana Farber Cancer Institute; Muhammad M. Mukhtar, Dana Farber Cancer Institute; Nagadenahalli B. Siddappa, Emory University; Samir K. Lakhashe, Dana Farber Cancer Institute; Mikyung Kim, Dana Farber Cancer Institute; Ellis L. Reinherz, Dana Farber Cancer Institute; Sandeep Gupta, University of California Irvine; Donald N. Forthal, University of California Irvine; Quentin Sattentau, University of Oxford; Francois Villinger, Emory University; Davide Corti, Humabs SAGL; Ruth M. Ruprecht, Dana Farber Cancer Institute
• Language: English
• Date: 2013-06-01
• Publisher: LIPPINCOTT WILLIAMS & WILKINS
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Wolters Kluwer Health; Lippincott Williams & Wilkins.
• Final Published Version (URL): http://dx.doi.org/10.1097/QAD.0b013e328360eac6
• Title of Journal or Parent Work: AIDS
• Volume: 27
• Issue: 9
• Start Page: F13
• End Page: F20
• Grant/Funding Information: This work was supported by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) UCL-VDC grant 38637 (R.A.W.) and CAVD 50314 (E.L.R.), by NIH grants R37 AI34266 and R01 DE023049 (R.M.R.), P01 AI48240 (R.M.R. and S.-L.H.) and by ORIP P51 000165 awarded to the YNPRC and R24OD010947 (F.V.).
• Keywords: immunoglobulin A isotypes; IMMUNIZATION; Infectious Diseases; VIRUS; Science & Technology; Life Sciences & Biomedicine; NEUTRALIZING MONOCLONAL-ANTIBODIES; HIV neutralization; LOAD; PROTECTION; mucosal transmission; transcytosis; Immunology; virion capture; Virology; R5 SHIV
• Research Categories: Health Sciences, Immunology; Biology, Virology

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 30min 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.