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 I (H IV-I) activity of various 2',3'-dideoxynucleoside analogs (ddNs) in pe ripheral blood mononuclear cells (PBM) was studied. We demonstrate tha t the in vitro anti-EW-l activity of various ddNs varies profoundly an d that the divergent antiviral activity is related to the extent of an abolic phosphorylation of each ddN and its counterpart 2' deoxynucleos ide (dN). We also show that certain ddNs cause a reduction of their co unterpart dNTP formation in PBM in the following order: 2',3'-dideoxyc ytidine (ddC) >> 2',3'-didehydro-2',3'-dideoxythymidine (d4T), 3'-thia -2',3'-dideoxycytidine (3TC), 2'3'-dideoxyinosine (ddI), 2',3'-dideoxy guanosine (ddG) > 3'-azido-2',3'-dideoxythymidine (AZT) > 2'-beta-fluo ro-2',3'-dideoxyadenosine (F-ara-ddA). Based on the phosphorylation pr ofiles, anti-HIV-1 ddNs can be classified into two groups: (i) cell-ac tivation-dependent ddNs such as AZT and d4T that are preferentially ph osphorylated, 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'-dideoxyade nosine), F-ara-ddA, ddG, ddC, and 3TC that produce higher ratios of dd NTP/dNTP and exert more potent anti-HIV-1 activity in resting cells. T hese data should provide a basis for the elucidation of the mechanism of the divergent antiretroviral activity of ddNs.