Vol. 61, Issue 6, 1359-1365, June 2002

Inhibition of the Tax-Dependent Human T-Lymphotropic Virus Type I Replication in Persistently Infected Cells by the Fluoroquinolone Derivative K-37

Xin Wang, Hiroshi Miyake, Mika Okamoto, Mineki Saito, Jun-Ichi Fujisawa, Yuetsu Tanaka, Shuji Izumo, and Masanori Baba

Division of Human Retroviruses (X.W., H. M., M.O., M.B.), Division of Molecular Pathology and Genetic Epidemiology (S.I.), Center for Chronic Viral Diseases, Third Department of Internal Medicine (M.S.), Faculty of Medicine, Kagoshima University; Kagoshima, Japan; Department of Microbiology, Kansai Medical University, Moriguchi, Japan (J.F.); and Department of Infectious Disease and Immunology, Okinawa-Asia Research Center of Medical Science, Faculty of Medicine, Ryukyu University, Okinawa, Japan (Y.T.)

In the search for anti-human T-lymphotropic virus type-I (HTLV-I) compounds, we have evaluated several compounds for their inhibitory effects on HTLV-I replication in cell cultures. Among the test compounds, the fluoroquinolone derivative 7-(3,4-dehydro-4-phenyl-1-piperidinyl)-1,4-dihydro-6-fluoro-1-methyl-8- trifluoromethyl-4-oxoquinoline-3-carboxylic acid (K-37) was found to be a potent and selective inhibitor of HTLV-I replication in persistently infected cells, such as MT-2 and MT-4. When the cells were cultured in the presence of various concentrations of the compound, the 50% effective concentrations of K-37 for HTLV-I p19 antigen production were 0.44 and 0.24 µM in MT-2 and MT-4 cells, respectively. K-37 did not affect the viability and proliferation of these cells at these concentrations, and its 50% cytotoxic concentrations to MT-2 and MT-4 cells were 5.7 and 1.1 µM, respectively. The compound also showed selective inhibition of HTLV-I production in peripheral blood mononuclear cells obtained from patients with HTLV-I-associated myelopathy/tropical spastic paraparesis. Quantitative reverse transcription-polymerase chain reaction analysis revealed that K-37 selectively suppressed viral mRNA synthesis in MT-2 cells in a dose-dependent fashion. Furthermore, K-37 could inhibit the endogenous Tax-induced HTLV-I long terminal repeat (LTR)-driven reporter gene expression in MT-2 cells. Western blot analysis confirmed the reduced expression of Tax in MT-2 cells exposed to K-37. In contrast, when Tax was introduced into cells not infected with HTLV-I with a plasmid under the control of human cytomegalovirus promoter, the compound did not affect Tax-induced HTLV-I LTR-driven reporter gene expression. These results suggest that the inhibition occurred at the level of HTLV-I LTR-driven Tax expression.