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. 2008 Oct;52(10):3532-41.
doi: 10.1128/AAC.01361-07. Epub 2008 Mar 3.

Inhibitors of strand transfer that prevent integration and inhibit human T-cell leukemia virus type 1 early replication

Samira Rabaaoui  1 , Fatima Zouhiri, Agnès Lançon, Hervé Leh, Jean d'Angelo, Eric Wattel
Affiliations

Inhibitors of strand transfer that prevent integration and inhibit human T-cell leukemia virus type 1 early replication

Samira Rabaaoui et al. Antimicrob Agents Chemother. 2008 Oct.

Abstract

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 that there is no therapy for the prevention and/or treatment of HTLV-1-associated diseases in infected individuals. HTLV-1 and human immunodeficiency virus type 1 (HIV-1) integrases, the enzymes that specifically catalyze the integration of these retroviruses in host cell DNA, share important structural properties, suggesting that compounds that inhibit HIV-1 integration could also inhibit HTLV-1 integration. We developed quantitative assays to test, in vitro and ex vivo, the efficiencies of styrylquinolines and diketo acids, the two main classes of HIV-1 integrase inhibitors. The compounds were tested in vitro in an HTLV-1 strand-transfer reaction and ex vivo by infection of fresh peripheral blood lymphocytes with lethally irradiated HTLV-1-positive cells. In vitro, four styrylquinoline compounds and two diketo acid compounds significantly inhibited HTLV-1 integration in a dose-dependent manner. All compounds active in vitro decreased cell proliferation ex vivo, although at low concentrations; they also dramatically decreased both normalized proviral loads and the number of integration events during experimental ex vivo primary 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 the prevention and treatment of HTLV-1-associated diseases.

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Figures

FIG. 1.
FIG. 1.
SQLs and DKA used for inhibition of HTLV-1 integration.
FIG. 2.
FIG. 2.
Targeting of HTLV-1 integration in vitro. (A) In vitro strand-transfer reactions catalyzed by HTLV-1 IN were performed with synthetic viral and target DNA molecules and various concentrations of SQLs or DKAs. The reaction products were quantified by fluorescent PCR. (B) Fluorescent PCR quantification of HTLV-1 strand transfer in the presence of increasing concentrations (0, 2, 5, and 10 μM) of the SQL derivative FZ41. Experiments were performed in triplicate, as shown by the electropherogram. Each peak represents a hot spot for HTLV-1 integration within the target DNA (see the text for details). (C) Concentration-dependent inhibition of the strand-transfer reaction catalyzed by recombinant HTLV-1 IN in the presence of compounds FZ41 and FZ149. The mean peak intensities from triplicate experiments were plotted as a function of the corresponding inhibitor concentrations.
FIG. 3.
FIG. 3.
Distribution of HTLV-1 integration and clonality during experimental infection of PBMCs with irradiated HTLV-1-positive MT2 cells. Inverse PCRs were carried out with DNA extracted from MT2 cells (lane MT2), from PBMCs before coculture (lane PBMC) and after coculture with irradiated MT2 cells (lane PBMC + MT2), as detailed in the text. The DNA of peripheral blood lymphocytes obtained from an additional uninfected donor served as a negative control (lane Control). Lane M, molecular weight marker.
FIG. 4.
FIG. 4.
Altered growth kinetics of PBMCs cocultured with irradiated HTLV-1-positive MT2 cells in the presence of various concentrations (0, 50, 100, and 250 μM) of SQLs (compounds KH161, FZ149, and FZ41) or DKAs (compounds L-731,988 and L-839,616). Cell preparation and coculture were performed as detailed in the text. x axis, time (t) that has elapsed from coculture (days); y axis, cell counts (106).
FIG. 5.
FIG. 5.
Effects of IN inhibitors on HTLV-1 proviral loads after coculture of PBMCs with irradiated HTLV-1-positive MT2 cells in the presence of 0, 50, and 100 μM of SQLs or DKAs. DNA was extracted at 7 days of coculture, and for each concentration, real-time quantitative PCR was carried out in triplicate, as detailed in the text. In the absence of compound, proviral loads were set to 100 units in order to better compare the effects of the compounds tested.
FIG. 6.
FIG. 6.
Effects of the IN inhibitors L-731,988 (A) and FZ149 (B) on HTLV-1 integration. (Left) Clonality of HTLV-1-positive cells over time in the presence of various concentrations (0, 50, or 100 μM) of inhibitor. Inhibitor concentrations and days of analysis are given at the bottom of the gel. (Right) Temporal (day 7, 14, and 21) fluctuations of growth kinetics, proviral loads, and HTLV-1 integration frequency as a function of IN inhibitor concentrations.
FIG. 6.
FIG. 6.
Effects of the IN inhibitors L-731,988 (A) and FZ149 (B) on HTLV-1 integration. (Left) Clonality of HTLV-1-positive cells over time in the presence of various concentrations (0, 50, or 100 μM) of inhibitor. Inhibitor concentrations and days of analysis are given at the bottom of the gel. (Right) Temporal (day 7, 14, and 21) fluctuations of growth kinetics, proviral loads, and HTLV-1 integration frequency as a function of IN inhibitor concentrations.
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