Transgene expression by oncolytic adenoviruses is modulated by E1B19K deletion in a cell type-dependent manner.
Major strategies to increase oncolytic adenovirus efficacy, as required for clinical applications, are enhancing oncolysis by acceleration of virus release/spread and "arming" by insertion of therapeutic genes. We investigated whether these strategies can be effectively combined as it has been speculated that the arming approach rather benefits from delayed cell lysis and extended time for protein synthesis. We report that deleting adenoviral E1B19K results in an apoptosis-dependent early viral release and thus enhanced oncolysis in several tumor cells, but inhibits virus replication in others. In the former case, apoptosis induction and early cell lysis did not interfere with late transgene expression. Thus, transgene expression was dramatically increased over time due to better virus spread. In A549 cells, transgene expression by the E1B19K(-) virus at 5 days post-infection was higher than for the E1B19K(+) virus at 10 days. These properties may be of critical importance in patients, where time for virus spread is limited.
Helmholtz-University Group Oncolytic Adenoviruses, German Cancer Research Center and Heidelberg University Hospital, Department of Dermatology, Heidelberg, Germany.
Stanimira
S
Rohmer
Christina
C
Quirin
Andrea
A
Hesse
Stefanie
S
Sandmann
Wibke
W
Bayer
Christel
C
Herold-Mende
Yosef S
YS
Haviv
Oliver
O
Wildner
Alexander H
AH
Enk
Dirk M
DM
Nettelbeck
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000256:Adenoviridae / Q000502:physiology*; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D030781:Organisms, Genetically Modified; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D014764:Viral Proteins