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′-β-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.