1. Peroxisome proliferator-activated receptor-gamma activation suppresses HIV-1 replication in an animal model of encephalitis.
- Author
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Potula R, Ramirez SH, Knipe B, Leibhart J, Schall K, Heilman D, Morsey B, Mercer A, Papugani A, Dou H, and Persidsky Y
- Subjects
- Animals, Brain virology, Cells, Cultured, HIV Long Terminal Repeat drug effects, HIV-1 drug effects, Humans, Macrophages virology, Mice, Mice, SCID, Models, Animal, NF-kappa B metabolism, PPAR gamma genetics, RNA Interference, RNA, Small Interfering administration & dosage, Rosiglitazone, Viremia drug therapy, Virus Replication drug effects, AIDS Dementia Complex drug therapy, PPAR gamma agonists, Thiazolidinediones therapeutic use
- Abstract
Objective: Poor penetration of antiretroviral therapy across the blood-brain barrier poses an impediment on control of HIV-1 infection in brain macrophages. Peroxisome proliferator-activated receptor (PPAR)-gamma, a member of the nuclear receptors family, regulates important physiological functions (including anti-inflammatory effects) in response to ligand-mediated activation. As PPARgamma agonists are rapidly absorbed by oral administration and efficiently permeate the blood-brain barrier, we hypothesized that PPARgamma stimulation may suppress HIV-1 replication., Design and Methods: We investigated the effect of PPARgamma ligand (rosiglitazone) on HIV-1 replication in human monocyte-derived macrophages and in vivo using a murine model (immunodeficient mice reconstituted with human lymphocytes and intracerebrally inoculated with HIV-1 infected macrophages) of HIV-1 encephalitis., Results: Treatment with rosiglitazone caused a significant decrease of virus infection in macrophages. PPARgamma stimulation inhibited virus replication by modulating NF-kappaB activation in a receptor-dependent manner, leading to downregulation of HIV-1 long terminal repeat (LTR) promoter activity and suppression of HIV-1 replication. These effects were PPARgamma specific as PPARgamma silencing or addition of PPARgamma antagonist abolished effects of PPARgamma stimulation on HIV-1 LTR and virus replication. Using a murine model for HIV-1 encephalitis, we demonstrated that PPARgamma ligand suppressed HIV-1 replication in macrophages in brain tissue and reduced viremia by 50%., Conclusion: In vitro data delineated the novel mechanism by which PPARgamma activation suppresses HIV-1 replication, and in vivo findings underscored the ability of PPARgamma agonists to reduce HIV-1 replication in lymphocytes and brain macrophages, thus offering a new therapeutic intervention in brain and systemic infection.
- Published
- 2008
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