Glenn Randall, Ph.D.

Hepatitis C Virus-Host Interactions

Research Summary

Our laboratory is interested in the molecular mechanisms that support persistent viral infections. Specifically, this research investigates the roles of hepatitis C virus (HCV)-host interactions in viral replication and pathogenesis.

HCV is a particularly relevant model because it has a notable ability to establish persistent infections, resulting in 170 million chronically infected people. Chronically infected individuals are a reservoir for new infections, as well as being at risk for progression to cirrhosis and hepatocellular carcinoma. Consequently, HCV infection is the leading indicator of liver transplant. Antiviral therapy shows sustained response in only about half of the treated patients. These factors have led to a push to develop new antiviral therapies and vaccines.

HCV research has long been hampered by the absence of an in vitro replication model. This obstacle has been recently hurdled with the development of an infectious HCV cell culture system. We have applied RNA interference (RNAi) to define host genes that are critical for viral infectivity. RNAi silencing the expression of either HCV or CD81, a cellular co-factor of viral infection, efficiently inhibits viral infection. We next performed a systematic RNAi screen of host genes that interact with HCV RNA or proteins. 24 host genes were identified that modulate HCV replication and virus production. These genes are likely to regulate diverse steps of the viral life cycle, including entry, viral translation, protein processing, replication, assembly, and egress of virus. Additionally, numerous genes involved in cellular stress response pathways regulate HCV replication. We are currently investigating the function and roles of a subset of these host genes in viral replication.

A second project investigates the control of HCV infection by the innate immune response. This began as an effort of collaborators from the University of Toronto to identify gene expression patterns that predict the success of anti-HCV therapy. They determined that the ISG15 protease USP18 is upregulated in the liver biopsies of patients who do not respond to interferon-α (IFN) therapy. We joined them to investigate the regulation of interferon antiviral activity by USP18, and to investigate the therapeutic potential of modulating USP18 activity.

Much research is currently investigating drugs to improve upon the current therapy of interferon and ribavirin, either by enhancing their effects or by supplanting them. We hypothesized that USP18 might hinder the ability of IFN to inhibit HCV replication. The siRNA knockdown of USP18 in human cells consistently potentiated the ability of interferon to inhibit HCV RNA replication and infectious virus particle production. USP18 knockdown also resulted in a number of cellular changes consistent with increased ISG15 protein modifications and sensitivity to interferon. Our current studies investigate the mechanism of enhanced antiviral response. This investigates whether the USP18 phenotype is ISG15-dependent and defines the signaling pathway by which USP18 regulates viral replication. These data suggest that USP18 modulates the anti-HCV type I IFN response, and is a possible therapeutic target for the treatment of HCV.

Dr. Randall contributes to the Microbiology program by assisting in the teaching of Medical Microbiology, Introduction to Virology, the Microbiology Seminar Series, serving as a mentor and sits on various thesis committees for Microbiology graduate students. 

Selected Papers