Inhibition of visna virus replication by 2',3'-dideoxynucleosides and acyclic nucleoside phosphonate analogs.

A series of acyclic nucleoside phosphonate (ANP) and 29,39-dideoxynucleoside (ddN) derivatives were evaluated for their inhibitory effects on visna virus replication and maedi/visna virus-induced syncytium formation in sheep choroid plexus cells. Most ANP derivatives inhibited virus replication and syncytium formation within a concentration range of 0.2 to 1.8 microM. Among the most active ANP derivatives ranked (R)-9-(2-phosphonomethoxypropyl)adenine, (R)-9-(2-phosphonomethoxypropyl)-2,6-diaminopurine, and (S)-9-(3-fluoro-2-phosphonomethoxypropyl)adenine. Of the ddN derivatives, 29,39-dideoxycytidine (ddCyd) proved to be the most inhibitory to visna virus-induced syncytium formation (50% effective concentration, 0.02 microM). The purine ddN analogs (i.e., 29,39-dideoxyinosine, 29,39-dideoxyadenosine, 29,39-dideoxyguanosine, and 2,6-diaminopurine-29,39-dideoxyribosine) were 10- to 30-fold less effective, and the thymidine derivatives 29,39-didehydro-29,39-dideoxythymidine (D4T) and 39-azido-29,39-dideoxythymidine (AZT) were more than 500-fold less inhibitory to visna virus than ddCyd. The 59-triphosphate forms of AZT and D4T were 100- to 600-fold more inhibitory to visna virus particle-derived reverse transcriptase than was the 59-triphosphate of ddCyd. The apparent discrepancy between the inhibitory effects of these ddN derivatives on virus replication and viral reverse transcriptase activity most likely reflects differences in the metabolic conversion of ddCyd versus D4T and AZT in sheep choroid plexus cells.