ZIDOVUDINE (AZT) RESISTANCE IN H9 CELLS DUE TO DECREASED TK EXPRESSION IS ASSOCIATED WITH HYPERMETHYLATION OF TK GENE

Abstract

AZT resistant human T-lymphoid H9 cells, deficient in TK gene expression, re-expressed TK mRNA and regained the ability to metabolize AZT by exposure to the demethylation agent azacytidine (AzaCd). Cytotoxic and anti-HIV-1 effects of AZT were increased in H9 AZT resistant cells treated with AzaCd when compared to untreated cells. This leads to the assumption that drug induced DNA hypermethylation was involved in the TK gene-silencing mechanism. Our results suggest approaches using modulation of gene methylation for increasing antiviral efficiency of drugs.

ACKNOWLEDGMENT

This work was generously supported by the foundations “Hilfe für krebskranke Kinder Frankfurt, e.V.” and “Frankfurter Stiftung für krebskranke Kinder.”