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, PGA(1) and PGA(2), inhibited HIV-1 replication in acutely infected human monocyte-derived macrophages (MDM). Because PGA(1) and PGA(2) have previously been shown to be peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, we examined the effect of synthetic PPARgamma agonists on HIV replication. The PPARgamma 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 PPARgamma wild type vectors and treatment with PPARgamma agonists inhibited HIV-1 promoter activity in U937 cells. Activation of PPARgamma also decreased HIV-1 mRNA stability following actinomycin D treatment. In summary, our experimental findings implicate PPARgamma as an important factor in the suppression of HIV-1 gene expression in MDM by cyPG. Thus natural and synthetic PPARgamma agonists may play a role in controlling HIV-1 infection in macrophages.
Highlights
AIDS is characterized by numerous immunological abnormalities, alterations in lymphocyte populations, and immunosuppression with subsequent development of opportunistic infections [1]
PPARγ is expressed upon activation of Peripheral blood monocytes (PBM), and their subsequent differentiation into monocyte-derived macrophages (MDM)
Treatment of MDM cultures with PGA1, and PGA2, at a concentration of 10 – 6 M at 16-24 h prior to infection with HIV-1 resulted in a significant decrease in viral replication, as assessed by Reverse transcriptase (RT) assay (Figure 1)
Summary
AIDS is characterized by numerous immunological abnormalities, alterations in lymphocyte populations, and immunosuppression with subsequent development of opportunistic infections [1]. Many of these changes can be attributed to alterations in mediator production including cytokines [2] and eicosanoids [3, 4]. In vitro production of PGE2 and thromboxane B2 by PBM from AIDS patients is increased relative to normal controls [11, 12]. Experimental infection of human PBM with HIV-1 results in increased production of PGE2 relative to uninfected control cultures [13,14,15,16]
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