The pyrimidine analog FNC inhibits cell proliferation and viral protein synthesis in HTLV-1-infected cells

Abstract

Human T-cell leukemia virus type 1 (HTLV-1), the first retrovirus to be identified, is the etiological agent of an aggressive clonal malignancy of mature CD4+ T lymphocytes known as adult T-cell leukemia (ATL). The prognosis of ATL patients remains poor despite the availability of a number of clinical chemotherapy drugs. In addition, HTLV-1-infected and ATL cells possess an intrinsic resistance to anticancer drugs. 2'-Deoxy-2'-β-fluoro-4'- azidocytidine (FNC) is a novel pyrimidine analog that is efficiently phosphorylated by cellular kinases and is a substrate for RNA and DNA polymerases. In the present study, the antiviral potential of FNC was investigated in HTLV-1-infected cell lines. Following FNC treatment, the HTLV-1-infected cells underwent G1 or S phase cell cycle arrest. FNC was also observed to reduce cell growth of the HTLV-1-infected cell lines in a dose-dependent manner. Notably, FNC was found to efficiently inhibit the expression of the viral proteins, Tax and p19Gag, in a dose- and time-dependent manner. Treatment with FNC and the protein biosynthesis inhibitor, cycloheximide (CHX), accelerated the inhibition of viral protein synthesis in the HTLV-1-infected cells. Collectively, these results demonstrated the efficient antiretroviral effect of FNC in HTLV-1-infected cells and indicate that FNC may be utilized as a valuable therapy in HTLV-1-infected patients and those with ATL.