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Abstract
The Diterpene TRIOL Inhibits HIV-1 Infection Mediated by Primary Isolates With Distinct Chemokine Receptor Usage.
Cirne-Santos C.C.1, Teixeira V.L.2, Barreto-de-Souza V.1, Castello-Branco L.R.1, Frugulhetti I.C.P.P.2, Bou-Habib D.C.1
1Oswaldo Cruz Foundation, Rio de Janeiro, Brazil, 2Fluminense Federal University, Niterói, Brazil
Introduction: We recently reported that the naturally occurring diterpene Triol inhibits the HIV-1 enzyme reverse transcriptase. Here we describe that Triol inhibits HIV-1 infection in human peripheral blood mononuclear cells (PBMCs) and macrophages regardless of the coreceptor usage of the viral isolates.
Methods: PBMCs were infected with primary R5-, X4- or R5X4-tropic isolates of HIV-1, and exposed to Triol during 7 days. Macrophages were exposed to R5- or R5X4-tropic isolates of HIV-1, and treated with Triol during 14 days. HIV-1 replication was assessed by measuring HIV-1 p24 Ag in culture supernatants. In some experiments, PBMCs or macrophages were pre-treated with Triol during 24 h and, then, exposed to HIV-1. U87 cells transfected with CD4 and with the coreceptors CCR5 or CXCR4 were infected by HIV-1, treated with Triol, and viral-mediated cytopathicity was evaluated by XTT assay after 5 days. The expression of CD4, CCR5 and CXCR4 molecules on PBMCs were analyzed by flow cytometry.
Results: Triol inhibited infection in PBMCs by a R5 virus in a dose-dependent manner (from 37% inhibition with 6 µM to 90% with 50 µM), and by X4 and R5X4 isolates (90% inhibition with 25 µM). Likewise, Triol inhibited HIV-1 infection in macrophages by R5 and R5X4 viruses in a dose-dependent manner, ranging from 80% to 95% inhibition with 3 µM to 50 µM. Triol (25 mM) also vigorously inhibited HIV-1 replication in cells transfected with chemokine receptors: 80% inhibition for R5 and 67% for X4 viruses. Pre-treatment of cells with Triol reduced HIV-1 replication in PBMCs (69% and 76% for R5- and X4-tropic isolates, respectively) and in macrophages (93% for a R5 isolate). Triol did not induce down-regulation of CD4, CCR5 and CXCR4 molecules in PBMCs.
Conclusions: Our results warrant further investigations on Triol pharmacokinetics and suggest that Triol could be considered as a potential compound for HIV-1 therapy.
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