Insertion of HIV-1 genes into Ad4ΔE3 vector abrogates increased pathogenesis in cotton rats due to E3 deletion

Abstract

Adenovirus type 5 (Ad5) E3 region proteins abrogate Ad pathogenicity in the lungs of cotton rats. Our use of Ad4-HIV E3-deleted (ΔE3) recombinants as vaccines necessitates further examination of these viruses for enhanced pathogenesis. Equivalent infectious doses of Ad4 wild-type (Ad4WT), Ad4ΔE3, and two recombinants: Ad4ΔE3HIVenv and Ad4ΔE3HIVgag, were inoculated intranasally into cotton rats. Ad4 viruses did not replicate in the lungs, but caused mild pathologic effects, including peribronchiolitis, bronchitis, alveolitis, and interstitial pneumonia. As found previously for Ad5, deletion of Ad4 E3 genes resulted in increased lung pathology. Surprisingly, insertion of HIV genes into this region significantly restored protection attributed to E3 gene products, diminishing overall pathologic effects to Ad4WT levels (P < 0.0001). Similarly, following administration of equivalent particle numbers of the four viruses, only Ad4ΔE3 caused increased overall pathology, while the two HIV recombinant viruses showed effects comparable to Ad4WT (P < 0.01). Our observation that Ad4ΔE3HIV recombinants are as safe in cotton rats as Ad4WT encourages their continued development as AIDS vaccines. © 2002 Elsevier Science.