Viruses and virus-based vectors represent a powerful tool for the delivery of recombinant molecules to cells. Our research has focused on the molecular biology of the paramyxovirus simian virus 5 (SV5), a non-segmented negative strand RNA virus that is non-pathogenic in most cells that we have examined. In addition to research projects involving virus replication and gene expression, we have developed two projects to utilize SV5 as a live virus vector. SV5 has inherent properties which we intend to exploit to develop a new class of versatile vectors that address important problems in cancer therapy and vaccine development.
Targeted Killing of Cancer Cells by Novel RNA Virus Vectors.
A major drawback to current systems for cancer therapy with recombinant viruses has been the inability to target and limit an infection by the virus to predetermined cancer cells or tissue. The long term goal of one of our projects is to develop novel SV5 vectors that have altered glycoproteins such that the specificity of the infection should be limited to cells that express specific tumor antigens on their surface.
In addition, we are currently engineering rSV5 to selectively kill tumor cells. We are pursuing approaches to convert SV5 from a non-cytopathic virus to a vector that will direct cell killing by mechanisms which are well understood and can be readily controlled. We have introduced the herpes TK gene into the SV5 genome such that cells infected with rSV5-tk will be susceptible to killing, but only when the pro-drug acyclovir is given. Thus, our future goal is to create a virus system in which the specificity of infection ispredetermined (e.g., cancer cells) and cell killing can be controlled (e.g., prodrug administration).
Development of Viral Vaccine Vectors.
Live virus vectors represent a powerful tool for vaccine purposes and SV5 has great potential as a novel class of RNA virus vectors. In a second project, we are addressing the innate and adaptive immune response elicited by infection with recombinant SV5 vectors. We are designing vectors to express different HIV antigens in order to elicit neutralizing antibody and antiviral CTL responses. This SV5 system represents a powerful system that will allow the selective expansion of host immune cells which can seek out and destroy virus infected cells. |