Anti-HIV IgA isotypes

Differential virion capture and inhibition of transcytosis are linked to prevention of mucosal R5 SHIV transmission

Jennifer D. Watkins, Anton M. Sholukh, Muhammad M. Mukhtar, Siddappa Nagadenahalli Byrareddy, Samir K. Lakhashe, Mikyung Kim, Ellis L. Reinherz, Sandeep Gupta, Donald N. Forthal, Quentin J. Sattentau, Francois Villinger, Davide Corti, Ruth M. Ruprecht

Research output: Contribution to journalArticle

81 Citations (Scopus)

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.

Original languageEnglish (US)
JournalAIDS
Volume27
Issue number9
DOIs
StatePublished - Jun 1 2013

Fingerprint

Transcytosis
Simian Immunodeficiency Virus
Macaca mulatta
Virion
Immunoglobulin A
HIV
Immunoglobulin G
Neutralizing Antibodies
Viruses
HIV-1
Monoclonal Antibodies
Passive Immunization
Virus Diseases
Viral Load
Vaccines
Pharmacokinetics
Epithelial Cells
anti-IgA

Keywords

  • HIV neutralization
  • Immunoglobulin A isotypes
  • Mucosal transmission
  • R5 SHIV
  • Transcytosis
  • Virion capture

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Anti-HIV IgA isotypes : Differential virion capture and inhibition of transcytosis are linked to prevention of mucosal R5 SHIV transmission. / Watkins, Jennifer D.; Sholukh, Anton M.; Mukhtar, Muhammad M.; Byrareddy, Siddappa Nagadenahalli; Lakhashe, Samir K.; Kim, Mikyung; Reinherz, Ellis L.; Gupta, Sandeep; Forthal, Donald N.; Sattentau, Quentin J.; Villinger, Francois; Corti, Davide; Ruprecht, Ruth M.

In: AIDS, Vol. 27, No. 9, 01.06.2013.

Research output: Contribution to journalArticle

Watkins, JD, Sholukh, AM, Mukhtar, MM, Byrareddy, SN, Lakhashe, SK, Kim, M, Reinherz, EL, Gupta, S, Forthal, DN, Sattentau, QJ, Villinger, F, Corti, D & Ruprecht, RM 2013, 'Anti-HIV IgA isotypes: Differential virion capture and inhibition of transcytosis are linked to prevention of mucosal R5 SHIV transmission', AIDS, vol. 27, no. 9. https://doi.org/10.1097/QAD.0b013e328360eac6
Watkins, Jennifer D. ; Sholukh, Anton M. ; Mukhtar, Muhammad M. ; Byrareddy, Siddappa Nagadenahalli ; Lakhashe, Samir K. ; Kim, Mikyung ; Reinherz, Ellis L. ; Gupta, Sandeep ; Forthal, Donald N. ; Sattentau, Quentin J. ; Villinger, Francois ; Corti, Davide ; Ruprecht, Ruth M. / Anti-HIV IgA isotypes : Differential virion capture and inhibition of transcytosis are linked to prevention of mucosal R5 SHIV transmission. In: AIDS. 2013 ; Vol. 27, No. 9.
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T2 - Differential virion capture and inhibition of transcytosis are linked to prevention of mucosal R5 SHIV transmission

AU - Watkins, Jennifer D.

AU - Sholukh, Anton M.

AU - Mukhtar, Muhammad M.

AU - Byrareddy, Siddappa Nagadenahalli

AU - Lakhashe, Samir K.

AU - Kim, Mikyung

AU - Reinherz, Ellis L.

AU - Gupta, Sandeep

AU - Forthal, Donald N.

AU - Sattentau, Quentin J.

AU - Villinger, Francois

AU - Corti, Davide

AU - Ruprecht, Ruth M.

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N2 - 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.

AB - 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.

KW - HIV neutralization

KW - Immunoglobulin A isotypes

KW - Mucosal transmission

KW - R5 SHIV

KW - Transcytosis

KW - Virion capture

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