Inhibition of human T-lymphotropic virus type I gene expression by the Streptomyces-derived substance EM2487.
EM2487, a Streptomyces-derived substance, has previously been shown to inhibit HIV-1 replication in both acutely and chronically infected cells. In this study, we found that EM2487 was also a selective inhibitor of human T-lymphotropic virus type I (HTLV-I) replication in persistently infected cells. Its 50% effective concentrations for HTLV-I p19 antigen production were 3.6 and 1.2 microM in MT-2 and MT-4 cells, respectively. However, the compound did not reduce cell proliferation and viability at these concentrations. The 50% cytotoxic concentrations of EM2487 were 30.6 and 5.7 microM in MT-2 and MT-4 cells, respectively. The compound also displayed 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 PCR analysis revealed that EM2487 selectively suppressed HTLV-I mRNA synthesis in MT-2 cells in a dose-dependent fashion. However, the compound did not inhibit endogenous Tax-induced HTLV-I long terminal repeat-driven reporter gene expression. Furthermore, intracellular Tax accumulation was not suppressed in MT-2 cells exposed to EM2487. These results suggest that the inhibition occurred at the viral transcription level, but it cannot be attributed to the inhibition of the Tax function.
Wang
X
X
Division of Human Retroviruses, Center for Chronic Viral Diseases, Faculty of Medicine, Kagoshima University, Japan.
Okamoto
M
M
Kawamura
M
M
Izumo
S
S
Baba
M
M
D000998:Antiviral Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D016356:Gene Products, tax / Q000378:metabolism; D005814:Genes, Viral / Q000235:genetics; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D015394:Molecular Structure; D010755:Organophosphates / Q000737:chemistry / Q000494:pharmacology*; D015493:Paraparesis, Tropical Spastic / Q000821:virology; D013302:Streptomyces / Q000737:chemistry*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014529:Uridine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; C400941:EM 2487; D016356:Gene Products, tax; D010755:Organophosphates; D014529:Uridine