In vivo anti-HIV activity of the heparin-activated serine protease inhibitor antithrombin III encapsulated in lymph-targeting immunoliposomes.
Endogenous serine protease inhibitors (serpins) are anti-inflammatory mediators with multiple biologic functions. Several serpins have been reported to modulate HIV pathogenesis, or exhibit potent anti-HIV activity in vitro, but the efficacy of serpins as therapeutic agents for HIV in vivo has not y...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0048234&type=printable |
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| author | Mohammed Asmal James B Whitney Corinne Luedemann Angela Carville Robert Steen Norman L Letvin Ralf Geiben-Lynn |
| author_facet | Mohammed Asmal James B Whitney Corinne Luedemann Angela Carville Robert Steen Norman L Letvin Ralf Geiben-Lynn |
| author_sort | Mohammed Asmal |
| collection | DOAJ |
| description | Endogenous serine protease inhibitors (serpins) are anti-inflammatory mediators with multiple biologic functions. Several serpins have been reported to modulate HIV pathogenesis, or exhibit potent anti-HIV activity in vitro, but the efficacy of serpins as therapeutic agents for HIV in vivo has not yet been demonstrated. In the present study, we show that heparin-activated antithrombin III (hep-ATIII), a member of the serpin family, significantly inhibits lentiviral replication in a non-human primate model. We further demonstrate greater than one log(10) reduction in plasma viremia in the nonhuman primate system by loading of hep-ATIII into anti-HLA-DR immunoliposomes, which target tissue reservoirs of viral replication. We also demonstrate the utility of hep-ATIIII as a potential salvage agent for HIV strains resistant to standard anti-retroviral treatment. Finally, we applied gene-expression arrays to analyze hep-ATIII-induced host cell interactomes and found that downstream of hep-ATIII, two independent gene networks were modulated by host factors prostaglandin synthetase-2, ERK1/2 and NFκB. Ultimately, understanding how serpins, such as hep-ATIII, regulate host responses during HIV infection may reveal new avenues for therapeutic intervention. |
| format | Article |
| id | doaj-art-b4b4669a1e3f48659bafbd7de8d40d87 |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-b4b4669a1e3f48659bafbd7de8d40d872025-08-20T03:08:21ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-01711e4823410.1371/journal.pone.0048234In vivo anti-HIV activity of the heparin-activated serine protease inhibitor antithrombin III encapsulated in lymph-targeting immunoliposomes.Mohammed AsmalJames B WhitneyCorinne LuedemannAngela CarvilleRobert SteenNorman L LetvinRalf Geiben-LynnEndogenous serine protease inhibitors (serpins) are anti-inflammatory mediators with multiple biologic functions. Several serpins have been reported to modulate HIV pathogenesis, or exhibit potent anti-HIV activity in vitro, but the efficacy of serpins as therapeutic agents for HIV in vivo has not yet been demonstrated. In the present study, we show that heparin-activated antithrombin III (hep-ATIII), a member of the serpin family, significantly inhibits lentiviral replication in a non-human primate model. We further demonstrate greater than one log(10) reduction in plasma viremia in the nonhuman primate system by loading of hep-ATIII into anti-HLA-DR immunoliposomes, which target tissue reservoirs of viral replication. We also demonstrate the utility of hep-ATIIII as a potential salvage agent for HIV strains resistant to standard anti-retroviral treatment. Finally, we applied gene-expression arrays to analyze hep-ATIII-induced host cell interactomes and found that downstream of hep-ATIII, two independent gene networks were modulated by host factors prostaglandin synthetase-2, ERK1/2 and NFκB. Ultimately, understanding how serpins, such as hep-ATIII, regulate host responses during HIV infection may reveal new avenues for therapeutic intervention.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0048234&type=printable |
| spellingShingle | Mohammed Asmal James B Whitney Corinne Luedemann Angela Carville Robert Steen Norman L Letvin Ralf Geiben-Lynn In vivo anti-HIV activity of the heparin-activated serine protease inhibitor antithrombin III encapsulated in lymph-targeting immunoliposomes. PLoS ONE |
| title | In vivo anti-HIV activity of the heparin-activated serine protease inhibitor antithrombin III encapsulated in lymph-targeting immunoliposomes. |
| title_full | In vivo anti-HIV activity of the heparin-activated serine protease inhibitor antithrombin III encapsulated in lymph-targeting immunoliposomes. |
| title_fullStr | In vivo anti-HIV activity of the heparin-activated serine protease inhibitor antithrombin III encapsulated in lymph-targeting immunoliposomes. |
| title_full_unstemmed | In vivo anti-HIV activity of the heparin-activated serine protease inhibitor antithrombin III encapsulated in lymph-targeting immunoliposomes. |
| title_short | In vivo anti-HIV activity of the heparin-activated serine protease inhibitor antithrombin III encapsulated in lymph-targeting immunoliposomes. |
| title_sort | in vivo anti hiv activity of the heparin activated serine protease inhibitor antithrombin iii encapsulated in lymph targeting immunoliposomes |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0048234&type=printable |
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