Department of Surgery Research

 Feng Yao, Ph.D.
 Division of Plastic Surgery   
   


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A recombinant herpes simplex virus (HSV) capable of inhibiting its own replication as well as replication of wild-type HSV would greatly increase its safety as a general purpose vector for in vivo gene transfer, anti-tumor therapy, and a viral vaccine against HSV infection.  In an attempt to generate an HSV-1 recombinant that encodes anti-HSV specific activity such as the trans-dominant negative mutant polypeptide of HSV-1 origin binding protein, UL9-C535C, we developed a novel tetracycline inducible regulatory switch.  This technology is currently licensed by Invitrogen Inc. (The T-RExTM System).

By cloning gene encoding the UL9-C535C under the control of this newly established gene switch, we generated a novel anti-HSV-1 specific HSV-1 recombinant, CJ83193.  Of particular significance is that CJ83193 can function as a potent intracellular therapy against wild-type HSV-1 and HSV-2 infection in cell cultures and the replication of wild-type HSV-1 in the central nervous system (CNS) of mice.  Furthermore, CJ83193 can function as an effective prophylactic vaccine against wild-type HSV-1 infection in mice.   We are currently in the process of further developing CJ83193-derived HSV recombinants such that their safety and efficacy as vaccines against HSV infection can be significantly enhanced.

HSV-1 replicates in epithelial cells and establishes life-long latent infection in neuronal cell bodies within the sensory ganglia of infected individuals.  In light of its dual-life cycle and its ability to infect a broad range of mitotic and post mitotic cells, HSV-1 has gained attention as a potential genetic vehicle to deliver and express therapeutic genes in a variety of tissues.  Because of its large genome size, up to 30 –50 kb transgene can be packaged into recombinant HSV-1 vectors. 

We have established two new HSV-1 viral vector systems for in vivo and in vitro gene delivery.  First, an HSV-1 essential gene in CJ83193 have been deleted and replaced with a reporter Lac Z gene.  The resulting replication-defective and dominant-negative HSV-1 recombinant can serve as a safe and effective general immunization vector against other infectious disease or cancers.  Second, the tetR-mediated gene switch has been introduced into a novel replication-defective HSV-1 recombinant such that the levels and timing of therapeutic gene expression can be finely adjusted by tetracycline at the different stages of application.  Moreover, by cloning an essential HSV gene under the control of this switch, we have generated a HSV-1 recombinant whose infection can be controlled by tetracycline both in vitro and in vivo. The potential application of this newly developed HSV-1 as a novel oncolytic virus for tumor therapy will be investigated.