Short and long term dissemination of deletion mutants of adenovirus in permissive (cotton rat) and non-permissive (mouse) species

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Abstract
As a first step in the evaluation of the safety of replication-defective adenoviruses used as gene transfer vectors, the dissemination of wild-type (wt) adenovirus (Ad) type 5, Ad-d1327 (deleted for the E3 gene) and Ad-gp50 (deleted for E3 and E1A and therefore replication defective) 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, and virus isolation was undertaken after sacrifice of the animals 3 or 31 days after inoculation. E3 deletion had no significant effect on viral spread, whereas E1A deletion reduced it significantly. After intramuscular inoculation of the E3-/E1A- virus, it could be isolated only from the local lymph node. Intranasal inoculation led to a wider distribution including lungs, liver, kidneys and lymph nodes. The pattern of dissemination of the E3-/E1A- virus was the same in mice and cotton rats, providing indirect evidence of the lack of replication of this virus in this species permissive for the wt virus. However, in the case of infection with a wt strain in E3-/E1A- adenovirus-inoculated recipients, both viruses were found in lymph nodes. In this situation the risk of phenotypic complementation of the E1A gene remains to be studied further.

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