The mechanism of 3'-azido-2',3'-dideoxythymidine resistance to human lymphoid cells.
The human T-lymphoid cell line H9 resistant to 3'-azido-2',3'-dideoxythymidine (AZT) has a very low level of thymidine kinase (TK) expression which accounts for the failure of AZT to inhibit HIV-1 replication. In the present study DNA methylation and histone deacetylation as possible mechanisms of decreased TK gene expression in the resistant cells were investigated. The resistant cells expressed high levels of DNA methyltransferases (DNMTs) 3a and 3b. The DNA methylation inhibitor, 5-aza-cytidine (5-aza-C), increased TK gene expression and antiviral activity of AZT in the resistant cells, while histone deacetylase inhibitor trichostatin A (TSA) had no effect. The results suggest that hypermethylation of the TK gene but not histone deacetylation in AZT-resistant H9 cells accounts for decreased TK gene expression and failure of AZT to inhibit HIV-1 replication probably due to overexpression of DNMT 3a and 3b.
Institute of Medical Virology, Johann Wolfgang Goethe-University Frankfurt, D-60596 Frankfurt/Main, Germany.
Gerold
G
Hoever
Bettina
B
Groeschel
Prakash
P
Chandra
Hans W
HW
Doerr
Jindrich
J
Cinatl
D000107:Acetylation; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001483:Base Sequence; D002460:Cell Line; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D015254:DNA Modification Methylases / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004351:Drug Resistance; D015870:Gene Expression; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006657:Histones / Q000378:metabolism; D006801:Humans; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D013937:Thymidine Kinase / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology*
D019380:Anti-HIV Agents; D018076:DNA, Complementary; C000717967:DNMT3A protein, human; D006657:Histones; D015215:Zidovudine; D015254:DNA Modification Methylases; D000090205:DNA Methyltransferase 3A; D013937:Thymidine Kinase