| The replication of the retrovirus human T cell leukemia virus type 1 (HTLV-1) is linked to the development of lymphoid malignancies and inflammatory diseases. Data from in vitro, ex vivo, and in vivo studies have revealed that no specific treatment can prevent or block HTLV-1 replication and therefore prevent and/or treat HTLV-1 associated diseases in infected individuals. HTLV-1 and HIV-1 integrases, the enzymes that specifically catalyze the integration of these retroviruses in host cell DNA, share important structural properties, suggesting that compounds inhibiting HIV-1 integration could also inhibit HTLV-1 integration. We developed quantitative assays to test, in vitro and ex vivo, the efficiency of styrylquinolines and diketo acids, the two main classes of HIV-1 integrase inhibitors. Compounds were tested in vitro on HTLV-1 strand-transfer reaction and ex vivo on infection of fresh peripheral blood lymphocytes with lethally irradiated HTLV-1 positive cells. In vitro, 4 styrylquinoline and 2 diketo acid compounds significantly inhibited HTLV-1 integration in a dose-dependent manner. All compounds active in vitro decreased cell proliferation ex vivo, though at low concentrations; they also dramatically decreased both normalized proviral loads and the number of integration events during experimental ex vivo primo infection. Accordingly, diketo acids and styrylquinolines are the first drugs that produce a specific negative effect on HTLV-1 replication in vitro and ex vivo, suggesting their potential efficiency for preventing and treating HTLV-1 associated diseases. |
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