Peroxisome proliferator-activated receptor γ agonists inhibit HIV-1 replication in macrophages by transcriptional and post-transcriptional effects

Abstract

Previous studies have demonstrated that cyclopentenone prostaglandins (cyPG) inhibit human immunodeficiency virus type 1 (HIV-1) replication in various cell types. We investigated the role of PG in the replication of HIV-1 in primary macrophages. The cyPG, PGA1 and PGA2, inhibited HIV-1 replication in acutely infected human monocyte-derived macrophages (MDM). Because PGA1 and PGA2 have previously been shown to be peroxisome proliferator-activated receptor γ (PPARγ) agonists, we examined the effect of synthetic PPARγ agonists on HIV replication. The PPARγ agonist ciglitazone inhibited HIV-1 replication in a dose-dependent manner in acutely infected human MDM. In addition, cyPG and ciglitazone reduced HIV replication in latently infected and viral entry-independent U1 cells, suggesting an effect at the level of HIV gene expression. Ciglitazone also suppressed HIV-1 mRNA levels as measured by reverse transcriptase PCR, in parallel with the decrease in reverse transcriptase activity. Co-transfection of PPARγ wild type vectors and treatment with PPARγ agonists inhibited HIV-1 promoter activity in U937 cells. Activation of PPARγ also decreased HIV-1 mRNA stability following actinomycin D treatment. In summary, our experimental findings implicate PPARγ as an important factor in the suppression of HIV-1 gene expression in MDM by cyPG. Thus natural and synthetic PPARγ agonists may play a role in controlling HIV-1 infection in macrophages.