Incorporation of the B18R gene of vaccinia virus into an oncolytic herpes simplex virus improves antitumor activity.
Interferon (IFN) antiviral defense mechanism plays a critical role in controlling virus infection. It thus represents a formidable hurdle for virotherapy. Despite the reported ability of herpes simplex virus (HSV) to counteract this defense, the duration and extent of HSV infection in vivo is still largely dictated by host's IFN activity status. Because the HSV genes that have been reported to block IFN activity mainly act intracellularly, we hypothesized that their inhibitory effect could be enhanced by exploiting a gene whose product acts extracellularly. The B18R gene from vaccinia virus encodes a secreted decoy receptor with a broad antagonizing effect against type I IFNs. We therefore cloned B18R into an HSV-1-based oncolytic virus to generate Synco-B18R. In the presence of increased IFN levels in vitro, Synco-B18R largely retained its oncolytic effect, whereas the tumor-killing ability of the parental virus, Synco-2D, was severely compromised. When injected intratumorally in vivo, Synco-B18R showed significantly greater oncolytic activity than Synco-2D. Our results suggest that incorporation of the vaccinia virus B18R gene can safely potentiate the antitumor effect of an oncolytic HSV, and that similar strategies may be useful with other types of oncolytic viruses.
Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas 77204, USA.
Xinping
X
Fu
Armando
A
Rivera
Lihua
L
Tao
Xiaoliu
X
Zhang
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D005260:Female; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007372:Interferons / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics* / Q000502:physiology; D010957:Plasmids; D011995:Recombination, Genetic; D014616:Vaccinia virus / Q000235:genetics*; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics*; D014779:Virus Replication
D000998:Antiviral Agents; D014764:Viral Proteins; C067853:B18R protein, Vaccinia virus; D007372:Interferons