Abstract |
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.
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Authors | Mohammed Asmal, James B Whitney, Corinne Luedemann, Angela Carville, Robert Steen, Norman L Letvin, Ralf Geiben-Lynn |
Journal | PloS one
(PLoS One)
Vol. 7
Issue 11
Pg. e48234
( 2012)
ISSN: 1932-6203 [Electronic] United States |
PMID | 23133620
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Liposomes
- Serine Proteinase Inhibitors
- Serpins
- Antithrombin III
- Heparin
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Topics |
- Animals
- Antithrombin III
(pharmacology)
- CD4-Positive T-Lymphocytes
(cytology)
- Disease Models, Animal
- Female
- Gene Expression Profiling
- Gene Expression Regulation
- HIV Infections
(drug therapy)
- Heparin
(chemistry)
- Liposomes
(metabolism)
- Lymph
(metabolism)
- Macaca mulatta
- Mice
- Mice, Inbred C57BL
- Mice, Inbred NOD
- Mice, Knockout
- Mice, SCID
- Serine Proteinase Inhibitors
(pharmacology)
- Serpins
(chemistry)
- Virus Replication
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