Inhibition of HTLV-I induction and virus-induced syncytia formation by oligodeoxynucleotides.
HTLV-I is an exogenous human retrovirus that is a causative agent of adult T cell leukemia (ATL). In addition to the structural genes (gag, pol and env), a gene termed pX is postulated to be associated with leukemogenesis in ATL. Since no effective chemotherapy is currently available, it is important to find suitable therapeutic means against ATL. Here, we tested the inhibitory effect of antisense oligodeoxynucleotides (ODNs) on HTLV-I infection in different systems. ODNs were synthesized with the phosphorothioate backbone targeted to either structural genes or transactivator genes. The phosphorothioate ODNs were found to have two distinct target sites to exert their effect on HTLV-I infection: 1) Several ODNs, including sense ODNs and random oligomers, blocked syncytium formation induced by HTLV-I at a concentration of 0.1 microM. Their inhibitory effect on syncytium formation seemed to be exerted in a nonantisense manner, most probably due to their interaction with the cell membrane. 2) Efficient suppression by ODNs of gag gene expression after chemical induction was observed in HTLV-I-transformed T cells in an antisense manner. In this suppression, tax-antisense ODN showed virtually complete inhibition of gag protein expression, but not RNA expression, at the concentration of 0.1 microM, whereas tax-sense ODN displayed a weak inhibitory effect. Our results suggest that the influence of the phosphorothioate compound should be considered from the aspect of two separated mechanisms of antiviral activity, the effects on early (viral adsorption) and late (translation) phase infection.
Miyano-Kurosaki
N
N
Department of Microbiology, Tokyo Medical and Dental University, School of Medicine, Japan.
Koyanagi
Y
Y
Mizuguchi
M
M
Ohki
S
S
Makino
K
K
Yamamoto
N
N
D000818:Animals; D015683:Gene Products, gag / Q000037:antagonists & inhibitors; D005814:Genes, Viral / Q000187:drug effects*; D016355:Genes, pX / Q000187:drug effects*; D015726:Giant Cells / Q000821:virology*; D015486:HTLV-I Antigens; D015368:Human T-lymphotropic virus 1 / Q000254:growth & development*; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D051381:Rats; D015682:Retroviridae Proteins, Oncogenic / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured; D015678:Viral Structural Proteins / Q000235:genetics*; D014775:Virus Activation / Q000187:drug effects*; D054301:gag Gene Products, Human Immunodeficiency Virus
D015683:Gene Products, gag; D015486:HTLV-I Antigens; D016376:Oligonucleotides, Antisense; D015682:Retroviridae Proteins, Oncogenic; D015678:Viral Structural Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C060955:p19 protein, Human T-lymphotropic virus 1