Potent Inhibition of HIV Type 1 Replication by an Antiinflammatory Alkaloid, Cepharanthine, in Chronically Infected Monocytic Cells

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Abstract
Cepharanthine is a biscoclaurine alkaloid isolated from Stephania cepharantha Hayata and has been shown to have antiinflammatory, antiallergic, and immunomodulatory activities in vivo. As several inflammatory cytokines and oxidative stresses are involved in the pathogenesis of HIV-1 infection, we investigated the inhibitory effects of cepharanthine on tumor necrosis factor α (TNF-α)- and phorbol 12-myristate 13-acetate (PMA)-induced HIV-1 replication in chronically infected cell lines. Two chronically HIV-1-infected cell lines, Ul (monocytic) and ACH-2 (T lymphocytic), were stimulated with TNF-α or PMA and cultured in the presence of various concentrations of the compound. HIV-1 replication was determined by p24 antigen level. The inhibitory effects of cepharanthine on HIV-1 long terminal repeat (LTR)-driven gene expression and nuclear factor κB (NF-κB) activation were also examined. Cepharanthine dose dependently inhibited HIV-1 replication in TNF-α- and PMA-stimulated Ul cells but not in ACH-2 cells. Its 50% effective and cytotoxic concentrations were 0.016 and 2.2 μg/ml in PMA-stimulated Ul cells, respectively. Cepharanthine was found to suppress HIV-1 LTR-driven gene expression through the inhibition of NF-κB activation. These results indicate that cepharanthine is a highly potent inhibitor of HIV-1 replication in a chronically infected monocytic cell line. Since biscoclaurine alkaloids, containing cepharanthine as a major component, are widely used for the treatment of patients with various inflammatory diseases in Japan, cepharanthine should be further pursued for its chemotherapeutic potential in HIV-1-infected patients.