Raymond Taeyong Chung
Our laboratory has been focused on the mechanisms of HCV persistence and pathogenesis. Hepatitis C virus infects 170 million persons worldwide and is remarkable for its predilection for chronicity. It is also a leading cause of chronic liver disease, liver cancer, and the need for liver transplantation. We have focused our efforts in development of model systems supportive of HCV replication, elucidating some of the many mechanisms by which viral proteins subvert innate antiviral immunity, particularly type I IFN signaling. We have focused on the actions of HCV core protein, which induces the selective degradation and inhbition of STAT1 phosphorylation. We are also studying suppressors of cytokine signaling (particularly SOCS3) andtheir interaction with IFN signaling in chronic HCV. Another avenue our laboratory has taken is a high throughput screen for small molecules that regulate HCV infection using a tractable replicon model. We have identified a number of small diversity oriented synthesis (DOS) molecules that inhibit HCV replication and are performing target identification to clarify mechanism of action. Similarly, we have used a whole genome siRNA library approach and identified several dozen host genes that participate in HCV replication. These include proteins involved in the secretory pathway and facilitation of intracellular lipid transport We believe that these approaches will add to our understanding of the underpinnings of HCV replication and lead to novel strategies to interrupt its lifecycle.
We have also been interested in understanding the basis for the observation of more progressive HCV-related liver disease in HIV-infected persons, despite the lack of liver tropism for HIV. We have found that HIV (gp120) can upregulate HCV replication through chemokine receptor-dependent means, and that this upregulation of HCV replication is TGF-beta mediated. This finding may help to explain both the increased levels of HCV replication observed in HIV, but also the acceleration of hepatic fibrosis. We are currently studying the mechanisms by which viral proteins induce TGF-beta and, in turn, fibrogenesis.
Boston, MA 2114