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Journal of Virology, July 2006, p. 6993-7008, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.00365-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Evaluating Replication-Defective Vesicular Stomatitis Virus as a Vaccine Vehicle

Department of Microbiology and Immunology, University of Miami School of Medicine and Sylvester Comprehensive Cancer Center, Miami, Florida

Received 21 February 2006/ Accepted 2 May 2006

We have generated replication-competent (VSV-C/E1/E2) and nonpropagating (VSVG-C/E1/E2) vesicular stomatitis virus (VSV) contiguously expressing the structural proteins of hepatitis C virus (HCV; core [C] and glycoproteins E1 and E2) and report on their immunogenicity in murine models. VSV-C/E1/E2 and VSVG-C/E1/E2 expressed high levels of HCV C, E1, and E2, which were authentically posttranslationally processed. Both VSV-expressed HCV E1-E2 glycoproteins were found to form noncovalently linked heterodimers and appeared to be correctly folded, as confirmed by coimmunoprecipitation analysis using conformationally sensitive anti-HCV-E2 monoclonal antibodies (MAbs). Intravenous or intraperitoneal immunization of BALB/c mice with VSV-C/E1/E2 or VSVG-C/E1/E2 resulted in significant and surprisingly comparable HCV core or E2 antibody responses compared to those of control mice. In addition, both virus types generated HCV C-, E1-, or E2-specific gamma interferon (IFN-)-producing CD8⁺ T cells, as determined by enzyme-linked immunospot (ELISPOT) analysis. Mice immunized with VSVG-C/E1/E2 were also protected against the formation of tumors expressing HCV E2 (CT26-hghE2t) and exhibited CT26-hghE2t-specific IFN--producing and E2-specific CD8⁺ T-cell activity. Finally, recombinant vaccinia virus (vvHCV.S) expressing the HCV structural proteins replicated at significantly lower levels when inoculated into mice immunized with VSV-C/E1/E2 or VSVG-C/E1/E2, but not with control viruses. Our data therefore illustrate that potentially safer replication-defective VSV can be successfully engineered to express high levels of antigenically authentic HCV glycoproteins. In addition, this strategy may therefore serve in effective vaccine and immunotherapy-based approaches to the treatment of HCV-related disease.

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