Pathogenesis

Infection with a virus of the family Flaviviridae can cause a wide variety of pathologies, including hemorrhagic fever (dengue virus and yellow fever virus), encephalitis (West Nile virus), hepatocellular carcinoma and immune cell abnormalities (hepatitis C virus). Understanding how these viruses cause disease, as well as efforts to develop vaccines and antiviral therapies, will require in vivo models of infection. For ethical, technical, and economic reasons, small animal models such as mice are the best suited for these essential studies. Unfortunately, some of the most significant Flaviviridae, including HCV, are primarily pathogens of humans, and do not infect mice. To overcome this limitation, we are developing and optimizing specialized mouse models. By engrafting mice with specific permissive cell types, we aim to drastically increase the efficiency of viral infection. Robust mouse models will be invaluable in developing an HCV vaccine as well as in preclinical safety and efficacy testing of antiviral drugs. The urgent need for preventative and therapeutic strategies for HCV and other Flaviviridae makes the development of these in vivo systems vitally important.

Fastidious host cell requirements, as well as limitation to a single infectious strain, mean HCV is also difficult to propagate in vitro. Since efficient HCV replication may depend on an authentic liver architecture, we are engineering cell culture systems that more accurately reflect the complexity of this organ. The mechanism by which HCV is restricted primarily to human cells is also not known. We have recently found evidence that tropism is likely not dictated solely at the level of cell entry, since CD81 molecules from several HCV-resistant animal species support uptake of pseudotyped particles. Identifying factors that influence permissivity to infection will help to further direct the development of small animal models and may elucidate novel targets for therapeutic intervention.