title: Insertion of HIV-1 genes into Ad4DeltaE3 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 (DeltaE3) recombinants as vaccines necessitates further examination of these viruses for enhanced pathogenesis. Equivalent infectious doses of Ad4 wild-type (Ad4WT), Ad4DeltaE3, and two recombinants: Ad4DeltaE3HIVenv and Ad4DeltaE3HIVgag, 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 Ad4DeltaE3 caused increased overall pathology, while the two HIV recombinant viruses showed effects comparable to Ad4WT (P < 0.01). Our observation that Ad4DeltaE3HIV recombinants are as safe in cotton rats as Ad4WT encourages their continued development as AIDS vaccines.
authors.affiliation: Basic Research Laboratory, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: L Jean
authors.initials: LJ
authors.lastname: Patterson
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Prince
authors.forename: Ersell
authors.initials: E
authors.lastname: Richardson
authors.forename: W Gregory
authors.initials: WG
authors.lastname: Alvord
authors.forename: Narender
authors.initials: N
authors.lastname: Kalyan
authors.forename: Marjorie
authors.initials: M
authors.lastname: Robert-Guroff
mesh_terms: D016915:AIDS Vaccines; D000256:Adenoviridae / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D000257:Adenoviridae Infections / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D017503:Adenovirus E3 Proteins / Q000235:genetics; D000818:Animals; D017353:Gene Deletion; D005822:Genetic Vectors; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008168:Lung / Q000473:pathology / Q000821:virology; D051381:Rats; D011995:Recombination, Genetic; D016205:Sigmodontinae; D014764:Viral Proteins / Q000235:genetics
chemical_list: D016915:AIDS Vaccines; D017503:Adenovirus E3 Proteins; D014764:Viral Proteins