SHORT AND LONG-TERM DISSEMINATION OF DELETION MUTANTS OF ADENOVIRUS IN PERMISSIVE (COTTON RAT) AND NONPERMISSIVE (MOUSE) SPECIES

As a first step in the evaluation of the safety of replication-defecti ve adenoviruses used as gene transfer vectors, the dissemination of wi ld-type (wt) adenovirus (Ad) type 5, Ad-d1327 (deleted for the E3 gene ) and Ad-gp50 (deleted for E3 and E1A and therefore replication defect ive) was studied in mice and cotton rats. Of each virus, 10(8) p.f.u. was inoculated, either by the intranasal or the intramuscular route, a nd virus isolation was undertaken after sacrifice of the animals 3 or 31 days after inoculation. E3 deletion had no significant effect on vi ral spread, whereas E1A deletion reduced it significantly. After intra muscular inoculation of the E3-/E1A-virus, it could be isolated only f rom the local lymph node. Intranasal inoculation led to a wider distri bution including lungs, liver, kidneys and lymph nodes. The pattern of dissemination of the E3-/E1A-virus was the same in mice and cotton ra ts, providing indirect evidence of the lack of replication of this vir us in this species permissive for the wt virus. However, in the case o f infection with a wt strain in E3-/E1A-adenovirus-inoculated recipien ts, both viruses were found in lymph nodes. In this situation the risk of phenotypic complementation of the E1A gene remains to be studied f urther.