Background:  Even in the era of HAART, control of HIV-1 replication in brain macrophages continues to pose a challenge due to poor penetration of HAART across blood brain barrier. Peroxisome proliferator-activated receptors (PPAR) (the nuclear hormone receptors and ligand-responsive transcription factors) participate in processes important for cell andtissue homeostasis. Of the 3 PPAR (a, b, and g), PPAR-g regulates pleiotropic anti-inflammatory pathways and can decrease HIV-1 replication in vitro. We hypothesized that PPAR-g stimulation may suppress virus infection in the blood and brain.

Methods:  An established murine model of HIV-1 encephalitis (NOD/SCID mice reconstituted with human lymphocytes and intracerebrally inoculated with HIV-1-infected monocyte-derived macrophages [MDM]) was used. Animals were fed daily with PPAR-g agonist, roziglitazone (10 mg/kg), or placebo. HIV-1 p24 levels and FACS (CD3/CD8/CD4) was performed on spleen and blood (week 1 to 3). At week 1 to 3 post-inoculation, mice were sacrificed and the number of human total MDM/virus-infected MDM, CD8⁺ lymphocytes was determined in the brain.

Results:  Equal numbers of lymphocytes were found in the spleen and blood of both animal groups by FACS indicating similar levels of engraftment. Numbers of CD8⁺ lymphocytes and CD68⁺ MDM were similar in brain of both groups at weeks 1 and 2. Rosiglitazone-treated mice demonstrated reduction of HIV-1 p24⁺ MDM as compared to controls at week 1 (130±35 vs 47±21, p <0.05). PPAR-g agonist treatment significantly suppressed virus replication, lowering a portion of HIV-1 p24⁺ MDM (30.2 % in placebo vs 17.0% rosiglitazone-fed mice at week 1 and 40.2 vs 23.2 % at week 2, p <0. 05). Furthermore, rosiglitazone-fed mice showed a 50% reduction of viremia as compared to control group (15,597±3567 vs 6921±1579 pg/mL, p <0. 05).

Conclusions:  These results indicate that PPAR-g stimulation leads to effective suppression of HIV-1 replication in blood lymphocytes and brain macrophages. Our findings suggest that the anti-viral properties of orally administered PPAR-g agonists offer new strategies for therapeutic intervention in HIV-1 encephalitis and systemic infection.