Hepatitis C virus [HCV], a member of the Flaviviridae, is a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Acute infection with HCV is associated with persistent viral replication in approximately 80-90% of cases, with an estimated 200 million people infected worldwide. Presently, the only effective therapy against HCV infection is type I interferon [IFN] currently in combination with the nucleoside analogue ribavirin. However, response rates vary from 5% to 50%, depending on race and gender, thus leaving many infected individuals untreatable. Presently, there is no vaccine for HCV and therefore a collective need to develop preventive strategies as well as new therapies. The search for effective vaccines is hampered, however, by the inability to grow candidate HCV vaccine preparations in vitro and by the prevalence of numerous HCV quasispecies that have evolved due to the virus lacking a proof reading mechanism while replicating. Since HCV cannot be efficiently manufactured for vaccine assessment, we have synthesized, in mammalian cells, highly immunogenic, non-infectious HCV-like particles comprised of the core, E1 and E2 products of HCV. This was achieved by cloning the core/El/E2 genomic region of HCV into the relatively simple, nonpathogenic negative-stranded virus, vesicular stomatitis virus (VSV). Following infection of tissue cultured mammalian cells with VSV/HCV recombinant viruses, high levels of authentic core/El/E2 HCV proteins were generated that autoassembled into HCV-virus-like particles (VLPs). Importantly, our preliminary data further indicates that VSV/HCV induced cell-mediated and humoral activity to all the structural proteins in immunized mice. Thus, our HCV expression system may have the capacity to generate effective, multivalent immune respones to a variety of HCV encoded proteins. Given this data, we aim to analyze the potency of the rVSVs system that expresses HCV gene products or purified HCV-like particles themselves, in vaccine studies designed to further evaluate whether robust cell-mediated and humoral responses can be safely and effectively obtained to multiple HCV epitopes.
| Greidinger, Eric L; Zang, YunJuan; Jaimes, Kimberly et al. (2006) A murine model of mixed connective tissue disease induced with U1 small nuclear RNP autoantigen. Arthritis Rheum 54:661-9 |
