Peroxisome proliferator-activated receptor-γ activation suppresses HIV-1 replication in an animal model of encephalitis

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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)-γ, a member of the nuclear receptors family, regulates important physiological functions (including anti-inflammatory effects) in response to ligand-mediated activation. As PPARγ agonists are rapidly absorbed by oral administration and efficiently permeate the blood–brain barrier, we hypothesized that PPARγ stimulation may suppress HIV-1 replication.Design and methods:We investigated the effect of PPARγ 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. PPARγ stimulation inhibited virus replication by modulating NF-κB 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 PPARγ specific as PPARγ silencing or addition of PPARγ antagonist abolished effects of PPARγ stimulation on HIV-1 LTR and virus replication. Using a murine model for HIV-1 encephalitis, we demonstrated that PPARγ 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 PPARγ activation suppresses HIV-1 replication, and in vivo findings underscored the ability of PPARγ agonists to reduce HIV-1 replication in lymphocytes and brain macrophages, thus offering a new therapeutic intervention in brain and systemic infection.

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