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

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 PPAR gamma agonists are rapidly absorbed by oral administration and efficiently permeate the blood-brain barrier, we hypothesized that PPAR gamma stimulation may suppress HIV-1 replication. Design and methods: We investigated the effect of PPAR gamma ligand (rosiglitazone) on HIV-1 replication in human monocyte-derived macrophages and in vivo using a muring model (immunodeficient mice reconstituted with human lymphocytes and intracerebrally inoculated with HIV-1 infected macrophages) of HIV-1 encephalitis. Results: Treatments with rosiglitazone caused a significant decrease of virus infection in macrophages. PPAR gamma stimulation inhibited virus replication by modulating NF-kappa B 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 PPAR gamma specific as PPAR gamma silencing or addition of PPAR gamma antagonist abolished effects of PPAR gamma stimulation on HIV-1 LTR and virus replication. Using a murine model for HIV-1 encephalitis, we demonstrated that PPAR gamma 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 PPAR gamma activation suppress HIV-1 replication, and in vivo findings underscored the ability of PPAR gamma agonists to reduce HIV-1 replication in lymphocytes and brain macrophages, thus offering a new therapeutic intervention in brain and systemic infection.