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Raymond Chung, MD, Director of Hepatology and Vice Chief of Gastroenterology, leads an NIH-funded Center for Human Immunology U19 Program, a consortium of eight projects centered on understanding the basis for the persistence of hepatitis C virus, an infection with a remarkable tendency to become chronic.
His laboratory has been committed to uncovering the strategies employed by hepatitis C virus to ensure its persistence in the liver, and the basis by which the infection causes liver scarring and cancer.
These studies include investigations into the basis for host genetic predispositions to successful responses to therapy with interferon.
His group has also been exploring the basis for HCV’s disruptive effects on lipid metabolism and insulin handling by the liver that lead to alterations in cholesterol levels and increased risk for diabetes.
Dr. Chung also leads the Mass General site of the NIH Hepatitis B Research Network, which is committed to long term study of optimal antiviral treatment strategies to prevent cirrhosis and liver cancer in persons chronically infected with this hepatitis virus.
Our laboratory projects include:
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 is the leading reason 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) and their interaction with IFN signaling in chronic HCV.
Interferon alfa, a type I IFN, exerts its broad antiviral effect through the induction of hundreds of host interferon stimulated genes (ISGs). However, the key genes operative against HCV are unknown.
We have been using functional genomic approaches to elucidate the key genes responsible for type I IFN action, in the hopes of refining treatments that retain interferon’s potency without producing the numerous systemic adverse effects that limit interferon therapy.
In separate studies, a genome wide association study (GWAS) has identified that a polymorphism in the IL28B (IFN lambda-3) locus that is a powerful predictor of success with interferon alfa therapy.
We are now exploring the functional basis for this finding using HCV infection models. By identifying the host mediators of IL28B action, we hope to further optimize treatment approaches to HCV.
Another avenue our laboratory has taken is a high throughput screen for small molecules that regulate HCV infection using a tractable replicon model.
To accomplish this, we have successfully employed two large scale screening strategies. Using a compound screening library, we have identified a number of small molecules that inhibit HCV replication and have successfully performed target identification to clarify their host cell targets.
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.
Unraveling the mechanisms underlying the acceleration of HCV pathogenesis by HIV coinfection
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 and its envelope protein gp120 can upregulate HCV replication through chemokine receptor-dependent means, and that this upregulation of HCV replication is TGF-b mediated.
This finding may help to explain both the increased levels of HCV replication observed in HIV, but also the acceleration of hepatic fibrosis observed in coinfection.
We are currently studying the mechanisms by which viral proteins induce TGF-beta and, in turn, contribute to hepatic fibrosis.
We have also found that HIV can promote hepatocyte apoptosis, highlighting another avenue for its contribution to accelerated pathogenesis.
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