Description of Research Expertise

Research Interests
The main interest of our translational research laboratory is the immune mechanisms of viral persistence and liver disease progression in patients infected with hepatitis C virus (HCV), an RNA virus with high rate of persistence (50-80%) associated with chronic necroinflammatory liver disease that can progress to liver cirrhosis and hepatocellular carcinoma.

Key words: HCV immune pathogenesis, HCV persistence, Viral escape, Viral persistence, Epitope mapping, Liver disease, T cell suppression, HIV/HCV coinfection, Alcohol.

Description of Research
Our research focuses on the immune pathogenesis of human HCV infection, testing the hypothesis that antiviral T cells play an important role in the outcome of HCV infection and identifying the relevant immunological features of successful HCV clearance or liver disease progression. In the absence of convenient animal model of HCV, we have identified valuable cohorts of persons with distinct clinical and virological outcome (e.g. acute, resolved, chronic infection with varying degrees of liver disease and treatment stage). Using patient samples in various in-vitro and ex-vivo T cell assays, we are addressing a number of hypotheses, including the following:

1. The outcome of HCV infection is determined by quantitatively and qualitatively distinct anviral T cell response. We are studying the relative frequency, repertoire, cytokine profile and activation level of HCV-specific CD4 and CD8 T cell response using both in vitro and ex vivo methods that allow determination of immunological hierarchy. In particular, we are examining the mechanisms whereby antiviral T cells are suppressed during chronic HCV infection. These studies will define the features of antiviral T response relevant in natural and therapeutic control of HCV.
2. Selection of T cell escape variants contribute to HCV persistence, disease progression and antiviral treatment resistance. HCV is a highly mutable virus that readily escapes recognition from neutralizing antibody. Based on the initial immunological analysis, we are looking for potential T cell escape variants to determine its prevalence and their effect in antiviral T cell response.
3. Alcohol and HIV accelerate the progression of HCV-associated liver disease by modulating the antiviral T cell response. The effect of these potential immunosuppressive factors in HCV-specific T cell response and the virus is currently being investigated.

We are also investigating the impact of various host and viral factors as well the interplay between the T cell subsets in HCV infection. It is hoped that the results of our study will be relevant in clinical care and vaccine development.

Rotation Projects
1. Effector T cell dysfunction in HCV persistence
2. Functional analysis and expansion of effector T cells in HCV infection
3. Identification of T cell epitopes using overlapping peptide library
4. Immunoregulatory factors in HCV persistence
5. Role of HCV gene products in regulatory T cells and effector T cell dysfunction
6. HCV-specific T cells in viral clearance and persistence
7. T cell escape mutation in patients with acute and chronic hepatitis C
8. Analysis of intrahepatic T cell response in HCV-infected patients
9. T cell response in patients undergoing antiviral therapy for chronic HCV infection
10. HCV immunogenetics

Lab personnel:
Hyosun Cho, PhD, Postdoctoral Researcher
Geoffrey DuFrayne, Research Specialist
Nobuhiro Nakamoto, MD, PhD, Postdoctoral Researcher
Mary Valiga, RN, Research Coordinator