Divergent anti-human immunodeficiency virus activity and anabolic phosphorylation of 2',3'-dideoxynucleoside analogs in resting and activated human cells.
The mechanism of divergent anti-human immunodeficiency virus type 1 (HIV-1) activity of various 2',3'-dideoxynucleoside analogs (ddNs) in peripheral blood mononuclear cells (PBM) was studied. We demonstrate that the in vitro anti-HIV-1 activity of various ddNs varies profoundly and that the divergent antiviral activity is related to the extent of anabolic phosphorylation of each ddN and its counterpart 2'-deoxynucleoside (dN). We also show that certain ddNs cause a reduction of their counterpart dNTP formation in PBM in the following order: 2',3'-dideoxycytidine (ddC) >> 2',3'-didehydro-2',3'-dideoxythymidine (d4T), 3'-thia-2',3'-dideoxycytidine (3TC), 2',3'-dideoxyinosine (ddI), 2',3'-dideoxyguanosine (ddG) > 3'-azido-2',3'-dideoxythymidine (AZT) > 2'-beta-fluoro-2',3'-dideoxyadenosine (F-ara-ddA). Based on the phosphorylation profiles, anti-HIV-1 ddNs can be classified into two groups: (i) cell-activation-dependent ddNs such as AZT and d4T that are preferentially phosphorylated, yield higher ratios of ddNTP/dNTP, and exert more potent anti-HIV-1 activity in activated cells than in resting cells; and (ii) cell-activation-independent ddNs including ddI (and 2',3'-dideoxyadenosine), F-ara-ddA, ddG, ddC, and 3TC that produce higher ratios of ddNTP/dNTP and exert more potent anti-HIV-1 activity in resting cells. These data should provide a basis for the elucidation of the mechanism of the divergent antiretroviral activity of ddNs.
Gao
W Y
WY
Experimental Retrovirology Section, National Cancer Institute, Bethesda, Maryland 20892.
Agbaria
R
R
Driscoll
J S
JS
Mitsuya
H
H
D002478:Cells, Cultured; D003842:Deoxycytidine Kinase / Q000378:metabolism; D016049:Didanosine / Q000494:pharmacology; D015224:Dideoxynucleosides / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology / Q000382:microbiology; D010766:Phosphorylation; D010835:Phytohemagglutinins / Q000494:pharmacology; D013937:Thymidine Kinase / Q000378:metabolism; D015215:Zidovudine / Q000494:pharmacology
D015224:Dideoxynucleosides; D010835:Phytohemagglutinins; D015215:Zidovudine; D013937:Thymidine Kinase; D003842:Deoxycytidine Kinase; D016049:Didanosine