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

Inhibition of HIV‐1 reverse transcriptase (RT) and HIV protease are effective mechanisms for anti‐retroviral agents, and the combined use of mechanistically different medications has markedly improved the treatment of HIV infected patients. The active metabolite of mercaptopurine and thioguanine (TG), deoxythioguanosine triphosphate, was shown to be incorporated into DNA by the polymerase function of HIV‐1 RT and then to abrogate RNA cleavage by HIV‐1 RNaseH. Treatment of human lymphocyte cultures with thioguanine produced substantial inhibition of HIV replication (IC50= 0.035 μM, IC95=15.4 μM), with minimal toxicity to host lymphocytes (< 10% at 15.4 μM TG, P< 0.000005). Furthermore, low concentrations of TG and zidovudine were synergistic in inhibiting HIV replication in human lymphocytes (synergy volume = 19 μM2%), without additive cytotoxicity to host lympho‐cytes. Thus, thiopurines are novel anti‐retroviral agents that alter the DNA‐RNA substrates for HIV RNaseH, thereby abrogating early stages of HIV replication.