INHIBITION OF VISNA VIRUS-REPLICATION BY 2',3'-DIDEOXYNUCLEOSIDES ANDACYCLIC NUCLEOSIDE PHOSPHONATE ANALOGS

A series of acyclic nucleoside phosphonate (ANP) and 2',3'-dideoxynucl eoside (ddN) derivatives were evaluated for their inhibitory effects o n visna virus replication and maedi/visna virus-induced syncytium form ation in sheep choroid plexus cells. Most ANP derivatives inhibited vi rus replication and syncytium formation within a concentration range o f 0.2 to 1.8 mu M. 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, 2',3'-dideoxycytidine (ddCyd) proved to be th e most inhibitory to visna virus-induced syncytium formation (50% effe ctive concentration, 0.02 mu M). The purine ddN analogs (i.e., 2',3'-d ideoxyinosine, 2',3'-dideoxyadenosine, 2',3'-dideoxyguanosine, and 2,6 -diaminopurine-2',3'-dideoxyribosine) were 10- to 30-fold less effecti ve, and the thymidine derivatives 2',3'-didehydro-2',3'-dideoxythymidi ne (D4T) and 3'-azido-2',3'-dideoxythymidine (AZT) were more than 500- fold less inhibitory to visna virus than ddCyd. The 5'-triphosphate fo rms of AZT and D4T were 100- to 600-fold more inhibitory to visna viru s particle-derived reverse transcriptase than was the 5'-triphosphate of ddCyd. The apparent discrepancy between the inhibitory effects of t hese ddN derivatives on virus replication and viral reverse transcript ase activity most likely reflects differences in the metabolic convers ion of ddCyd versus D4T and AZT in sheep choroid plexus cells.