DIFFERENTIAL ANTIVIRAL ACTIVITIES AND INTRACELLULAR METABOLISM OF 3'-AZIDO-3'-DEOXYTHYMIDINE AND 2',3'-DIDEOXYINOSINE IN HUMAN-CELLS

Dideoxynucleosides such as 3'-azido 3'-deoxythymidine (AZT) and 2',3'- dideoxyinosine (ddI) can effectively inhibit the replication of human immunodeficiency virus (HIV) in T lymphoid cells. There is evidence th at HIV can infect and replicate in other cells including monocytoid ce lls and macrophages. The present study compared the antiretroviral act ivities of ddI and AZT in three lineages of human cells, i.e., MOLT4 ( T lymphocytoid, CD4(+)), U937 (monocytoid, CD4(+)), and HT1080 (fibrob lastoid, CD4(-)) cells. Feline leukemia virus, a retrovirus that cause s immunodeficiency in cats, was used to infect the cells. The drug con centrations needed to reduce the viral p27 antigen titers in cell lysa tes by 50% (IC(50)s) were determined. The data show that AZT and ddI i nhibited viral replication in all three cell lines. The IC(50)s of AZT were 0.02, 1.75, and 2.31 mu M in MOLT4, HT1080, and U937 cells, resp ectively. For ddI, the IC(50)s were 4.31, 9.52, and 43.5 mu M, respect ively. These data indicate differential antiviral activities of ddI an d AZT in the different cells,vith the following rank order of drug sen sitivity: MOLT4 > HT1080 > U937. A study of the intracellular metaboli sm of [H-3]AZT and [H-3] ddI shows that the antiretroviral activities of AZT and ddI in the three cell lines correlated with the levels of t heir intracellular triphosphate metabolites.