Dioxolane Guanosine, the Active Form of the Prodrug Diaminopurine Dioxolane, Is a Potent Inhibitor of Drug-Resistant HIV-1 Isolates From Patients for Whom Standard Nucleoside Therapy Fails

Amdoxovir ([-]-β-D-2,6-diaminopurine dioxolane [DAPD]) is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against HIV-1. DAPD is deaminated in vivo by adenosine deaminase to (-)-β-D-dioxolane guanosine (DXG), a highly active anti-HIV compound. The median 50% effective concentrations (EC50) ± SD (representing antiviral activity against a laboratory-derived HIV-1 isolate) for DAPD and DXG in peripheral blood mononuclear cells were 4.0 ± 2.2 μmol/L and 0.25 ± 0.17 μmol/L, respectively. The 50% cytotoxic dose (CC50) of both DAPD and DXG was >500 μmol/L. Recombinant viruses and clinical isolates of HIV-1 from patients for whom NRTI therapy and/or nonnucleoside reverse transcriptase inhibitor (NNRTI) combination therapies failed remained susceptible to inhibition by DXG (less than fourfold change in EC50). Similar analysis showed that recombinant viruses harboring mutations known to confer resistance to NRTIs (zidovudine, lamivudine, and abacavir) and NNRTIs (efavirenz and nevirapine) as well as the multidrug resistance-associated mutation Q151M and double codon insertions (SS and SG) were also susceptible to inhibition by DXG. Resistance to DXG was observed only in recombinant isolates containing the 65R and 151M double mutations. Phenotypic analysis of a site-directed mutant containing only the 151M mutation demonstrated moderate resistance to DXG (