Anti-HIV IgA isotypes: differential virion capture and inhibition of transcytosis are linked to prevention of mucosal R5 SHIV transmission.
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,...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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2013
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| _version_ | 1826260623288172544 |
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| author | Watkins, J Sholukh, A Mukhtar, M Siddappa, N Lakhashe, S Kim, M Reinherz, E Gupta, S Forthal, D Sattentau, Q Villinger, F Corti, D Ruprecht, R |
| author_facet | Watkins, J Sholukh, A Mukhtar, M Siddappa, N Lakhashe, S Kim, M Reinherz, E Gupta, S Forthal, D Sattentau, Q Villinger, F Corti, D Ruprecht, R |
| author_sort | Watkins, J |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T19:08:36Z |
| format | Journal article |
| id | oxford-uuid:16035fb8-12f3-4697-bc51-8b72e449b32d |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T19:08:36Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:16035fb8-12f3-4697-bc51-8b72e449b32d2022-03-26T10:28:46ZAnti-HIV IgA isotypes: differential virion capture and inhibition of transcytosis are linked to prevention of mucosal R5 SHIV transmission.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:16035fb8-12f3-4697-bc51-8b72e449b32dEnglishSymplectic Elements at Oxford2013Watkins, JSholukh, AMukhtar, MSiddappa, NLakhashe, SKim, MReinherz, EGupta, SForthal, DSattentau, QVillinger, FCorti, DRuprecht, ROBJECTIVE: 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. |
| spellingShingle | Watkins, J Sholukh, A Mukhtar, M Siddappa, N Lakhashe, S Kim, M Reinherz, E Gupta, S Forthal, D Sattentau, Q Villinger, F Corti, D Ruprecht, R Anti-HIV IgA isotypes: differential virion capture and inhibition of transcytosis are linked to prevention of mucosal R5 SHIV transmission. |
| title | Anti-HIV IgA isotypes: differential virion capture and inhibition of transcytosis are linked to prevention of mucosal R5 SHIV transmission. |
| title_full | Anti-HIV IgA isotypes: differential virion capture and inhibition of transcytosis are linked to prevention of mucosal R5 SHIV transmission. |
| title_fullStr | Anti-HIV IgA isotypes: differential virion capture and inhibition of transcytosis are linked to prevention of mucosal R5 SHIV transmission. |
| title_full_unstemmed | Anti-HIV IgA isotypes: differential virion capture and inhibition of transcytosis are linked to prevention of mucosal R5 SHIV transmission. |
| title_short | Anti-HIV IgA isotypes: differential virion capture and inhibition of transcytosis are linked to prevention of mucosal R5 SHIV transmission. |
| title_sort | anti hiv iga isotypes differential virion capture and inhibition of transcytosis are linked to prevention of mucosal r5 shiv transmission |
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