Deoxythioguanosine triphosphate impairs HIV replication: a new mechanism for an old drug

Inhibition of HIV-1 reverse transcriptase (RT) and HIV protease are effecti ve mechanisms for anti-retroviral agents, and the combined use of mechanist ically different medications has markedly improved the treatment of HIV inf ected patients. The active metabolite of mercaptopurine and thioguanine (TG ), deoxythioguanosine triphosphate, was shown to be incorporated into DNA b y the polymerase function of HIV-1 RT and then to abrogate RNA cleavage by HIV-1 RNaseH. Treatment of human lymphocyte cultures with thioguanine produ ced substantial inhibition of HIV replication (IC50 = 0.035 muM, IC95 = 515 .4 muM), with minimal toxicity to host lymphocytes (<10% at 15.4 <mu>M TG, P<0.000005). Furthermore, low concentrations of TG and zidovudine were syne rgistic in inhibiting HIV replication in human lymphocytes (synergy volume= 9 <mu>M-2 %), without additive cytotoxicity to host lymphocytes. Thus, thio purines are novel anti-retroviral agents that alter the DNA-RNA substrates for HIV RNaseH, thereby abrogating early stages of HIV replication.