INHIBITORY EFFECT OF 9-(2-PHOSPHONYLMETHOXYETHYL)ADENINE ON VISNA VIRUS-INFECTION IN LAMBS - A MODEL FOR IN-VIVO TESTING OF CANDIDATE ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS DRUGS

The acyclic nucleoside phosphonate analog 9-(2-phosphonylmethoxyethyl) adenine (PMEA) was recently found to be effective as an inhibitor of v isna virus replication and cytopathic effect in sheep choroid plexus c ultures. To study whether PMEA also affects visna virus infection in s heep, two groups of four lambs each were inoculated intracerebrally wi th 10(6.3) TCID50 of visna virus strain KV1772 and treated subcutaneou sly three times a week with PMEA at 10 and 25 mg/kg, respectively. The treatment was begun on the day of virus inoculation and continued for 6 weeks. A group of four lambs were infected in the same way but were not treated. The lambs were bled weekly or biweekly and the leukocyte s were tested for virus. At 7 weeks after infection, the animals were sacrificed, and cerebrospinal fluid (CSF) and samples of tissue from v arious areas of the brain and from lungs, spleen, and lymph nodes were collected for isolation of virus and for histopathologic examination. The PMEA treatment had a striking effect on visna virus infection, wh ich was similar for both doses of the drug. Thus, the frequency of vir us isolations was much lower in PMEA-treated than in untreated lambs. The difference was particularly pronounced in the blood, CSF, and brai n tissue. Furthermore, CSF cell counts were much lower and inflammator y lesions in the brain were much less severe in the treated lambs than in the untreated controls. The results indicate that PMEA inhibits th e propagation and spread of visna virus in infected lambs and prevents brain lesions, at least during early infection. The drug caused no no ticeable side effects during the 6 weeks of treatment.