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HCV is a unique model system to study human viral infections, not only because it is one of the most clinically relevant chronic viral infections with a worldwide pandemic affecting more than 170 million people, but also of the dichotomy in its clinical course: While 80% of subjects will develop a life-long chronic infection, about 20% of subjects with acute HCV infection will complete eradicate the virus, usually within the first 6 months after infection. Most other infections that are studied in humans are either universally acute (influenza) or they generally persist (HIV, EBV, CMV). In addition, we are able to obtain tissue for analysis from the exclusive site of HCV replication, the liver. This makes HCV a model system for human immunology that should allow unique insights into the determinants of viral control and viral persistence.
The lab is the primary site of a NIH sponsored U19 HCV Collaborative Research Center “Immune Control and Evasion during Acute HCV Infection” (PI: Georg Lauer), and also a main project site in the U19 Collaborative Center for Human Immunology “Mechanisms of Immune Failure in Chronic Infection: Hepatitis C as a Key Paradigm”. Furthermore we are part of a Human Immunology Consortium “Optimizing Human T-Cell Responses to Prevent Chronic Infection” funded by the Dana Foundation and part of the Center for Inflammatory Bowel Disease at Massachusetts General Hospital.
Dr. Lauer has been interested in both clinical and scientific aspects of HCV for over 15 years, starting with his clinical training in Internal Medicine and Gastroenterology and laboratory work on HCV for his PhD in Medical Sciences in Germany. Since coming to the Massachusetts General Hospital as a postdoctoral fellow more than 10 years ago he has build, together with his colleague Arthur Kim several large research cohorts and research specimen repositories, including more than 800 subjects with acute and chronic HCV infection. The lab is mainly interested in the immunopathogenesis of hepatitis C virus (HCV) infection.
There are currently two major programs in the lab, one that focuses on the T-cell response during acute HCV infection, the other studying the T-cell response against HCV that persists in chronic HCV infection, especially in the liver:
In the first program, we are trying to understand the correlates of protection from persistent HCV infection as well as the mechanisms employed by the virus to circumvent immunological control. These studies aim to guide the development of preventative HCV vaccines. In our translational studies we are using samples from a cohort of over 200 patients with acute HCV infection, recruited locally, in the Massachusetts Prison System and through our long-term collaborators at the Istituto Oswaldo Cruz in Rio de Janeiro, Brazil. We have been at the forefront of comprehensively mapping and defining the CD8 and CD4 response in acute HCV infection, using ELISpot and extensive flow cytometry studies using class I and class II peptide multimers. We also have closely described the interaction between the T-cell response and viral evolution. Recently we have started ambitious new projects to introduce Systems Biology approaches into the studies of the HCV T-cell response. We are generating large sets of microarray data from HCV-specific T-cells in order to define the early mechanisms that are associated with successful or unsuccessful control of HCV.
Our second program is focused on responses that persist, but are obviously ineffective, in chronic HCV infection. By defining the mechanisms by which T-cells are rendered ineffective and potential avenues to restore viral control we hope to enable future immunotherapies for the treatment of established HCV infection. A main component of this effort is the study of T-cells derived from infected livers, the main site of HCV infection and replication. We are developing microscopy based assays that will characterize the network of infected hepatocytes, immune cells and stimulatory and inhibitory signals in-situ. We also analyze liver derived immune cells by flow cytometry and microarray analysis of defined T-cell populations.
Our key collaborators are:
Georg M. Lauer, MD PhD
Lizeng Qin, MD PhD
Donatella Ciuffreda, MD
Daniela Kroy, MD
Peter Foote, Research Technician
Garrett Hauck, Research Technician
Laura Reyor, Clinical Research Coordinator
Michelle Tomlinson, Clinical Research Coordinator
Helen Yang, Summer Student
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