Deletion of the E3-6.7K/gp19K region reduces the persistence of wild-type adenovirus in a permissive tumor model in Syrian hamsters.
A partial deletion of the adenovirus E3 region, comprising the overlapping 6.7K/gp19K genes, has been described for the incorporation of therapeutic genes in 'armed' oncolytic adenoviruses. This deletion allows the insertion of up to 2.5 kb genetic material into the virus and ensures strong expression of transgenes without reducing the replication and cytolytic potency of viruses in vitro. E3-gp19K and 6.7K proteins are involved in avoiding recognition and elimination of infected cells by the host immune system. Therefore, we have studied the effect of this deletion on the replication and transgene expression of the virus in immunocompetent models based on Syrian hamsters. Tumors were established by intrahepatic injection of pancreatic cancer cells with moderate (HaP-T1, HP-1) or low (H2T) permissivity for adenovirus replication. The wild-type human adenovirus 5 (Ad5) or a modified version containing the luciferase gene in the E3-6.7K/gp19K locus (Ad-WTLuc) were injected intratumorally. We found that elimination of Ad-WTLuc was faster than Ad5 in HaP-T1 and HP-1 tumors. In contrast, no differences were observed when the same tumor was established in severely immunocompromised NOD-scid IL2Rgamma(null) mice. In addition, virus-mediated luciferase expression was more stable in these animals. These results suggest that the lack of E3-6.7K/gp19K genes may accelerate the clearance of oncolytic adenoviruses in some immunocompetent tumor models.
Bortolanza
S
S
Division of Hepatology and Gene Therapy, CIMA, Foundation for Applied Medical Research, School of Medicine, University of Navarra, Pamplona 31008, Spain.
Bunuales
M
M
Alzuguren
P
P
Lamas
O
O
Aldabe
R
R
Prieto
J
J
Hernandez-Alcoceba
R
R
D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D017503:Adenovirus E3 Proteins / Q000235:genetics* / Q000276:immunology; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D004195:Disease Models, Animal; D017353:Gene Deletion; D015967:Gene Expression Regulation, Viral; D017930:Genes, Reporter; D016679:Genome, Viral; D006801:Humans; D007121:Immunocompetence; D008647:Mesocricetus; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy* / Q000821:virology; D050130:Oncolytic Virotherapy; D019076:Transgenes; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D017503:Adenovirus E3 Proteins