title: Anti-HIV IgA isotypes: differential virion capture and inhibition of transcytosis are linked to prevention of mucosal R5 SHIV transmission.
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.
  
  
  METHODS
  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.
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Watkins
authors.forename: Anton M
authors.initials: AM
authors.lastname: Sholukh
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Mukhtar
authors.forename: Nagadenahalli B
authors.initials: NB
authors.lastname: Siddappa
authors.forename: Samir K
authors.initials: SK
authors.lastname: Lakhashe
authors.forename: Mikyung
authors.initials: M
authors.lastname: Kim
authors.forename: Ellis L
authors.initials: EL
authors.lastname: Reinherz
authors.forename: Sandeep
authors.initials: S
authors.lastname: Gupta
authors.forename: Donald N
authors.initials: DN
authors.lastname: Forthal
authors.forename: Quentin J
authors.initials: QJ
authors.lastname: Sattentau
authors.forename: Francois
authors.initials: F
authors.lastname: Villinger
authors.forename: Davide
authors.initials: D
authors.lastname: Corti
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Ruprecht
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage* / Q000276:immunology; D000285:Administration, Rectal; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D018928:Immunity, Mucosal / Q000276:immunology; D007116:Immunization, Passive; D007070:Immunoglobulin A / Q000276:immunology*; D007413:Intestinal Mucosa / Q000821:virology; D008253:Macaca mulatta; D009500:Neutralization Tests; D012367:RNA, Viral / Q000097:blood; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control* / Q000635:transmission; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D057900:Transcytosis / Q000187:drug effects* / Q000502:physiology; D019562:Viral Load; D014771:Virion / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D007070:Immunoglobulin A; D012367:RNA, Viral