Decrease in Thymidylate Kinase Activity in Peripheral Blood Mononuclear Cells from HIV-Infected Individuals

Abstract

Nucleosides and nucleoside analogs are anabolised to their triphosphates by intracellular kinases. The anti-HIV analogue zidovudine (AZT) is phosphorylated by cytosolic thymidine kinase 1 (TK1), thymidylate kinase (dTMPK), and nucleoside diphosphate kinase. It is known that dTMPK is one of the rate-limiting steps in the activation of zidovudine. The activities of TK1, dTMPK, and deoxycytidine kinase (dCK) were determined in extracts of in vitro activated peripheral blood mononuclear cells from HIV-infected patients and healthy noninfected individuals. dTMPK activity was 10-fold lower and TK1 activity was five-fold lower in extracts from infected as compared to uninfected persons. Deoxycytidine kinase activities in the extracts from both groups were very similar. Differences in in vitro activation, as determined by flow cytometry, of the peripheral lymphocytes were not responsible for the decreased TK1 and dTMPK activities. A reduced level of intracellular azido-dideoxythymidinetriphosphate in activated mononuclear cells from HIV-infected patients was also observed. The low levels of TK1 and dTMPK in lymphocytes from HIV-infected patients may be related to the anergy phenomenon observed as a result of HIV infection. This effect should also be considered in the development of new anti-HIV drugs.