Optimizing Human T-Cell Responses to Prevent Chronic Viral Infection

W. Nicholas Haining, M.B., B.Ch.

Dana-Farber Cancer Institute

Funded in April, 2008: $600000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Optimizing Human T-Cell Responses to Prevent Chronic Infection

Nearly 170 million people around the world are infected with Hepatitis C virus (HCV), a virus that can cause liver failure and liver cancer.  In the U.S., chronic infection with HCV is the leading cause for liver transplantation.  There is no cure for the infection and no vaccine to prevent chronic HCV infection.  However, not everyone exposed to HCV develops persistent infection.  About 20% of persons acutely infected with HCV clear the virus within 6 months. The other 80% of infected individuals will develop persistent infection and are at risk for chronic hepatitis.  Currently we do not know why the immune response in some individuals is able to protect against the virus while in others it is not.

In this proposal, we aim to use cutting-edge technology to identify the molecular signature HCV-specific T cells that can protect against infection by comparing the gene expression patterns of protective versus non-protective T cells.  We will also take advantage of our recent advances in cross-species gene expression comparisons and the use of a mouse model of chronic viral infection to help distill the molecular signature obtained in humans down to the essence of a gene expression profile in T cells associated with viral control versus chronic infection. These gene-expression patterns will allow us develop a predictive signature of gene expression profiles in subjects who will develop chronic infection and those who will be cleared of the virus.  Moreover, this human:mouse comparison will provide a tool to understand the basic molecular mechanisms that account for the failure of viral immunity in some people.  Finally, we will use the protective pattern of genes as a target to develop new drugs to improve the immune response against chronic viral infections.

If successful, this approach could improve the diagnosis and treatment not only of HCV, but also of other chronic viral infections including HIV, tuberculosis, and malaria.

ABSTRACT

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Optimizing Human T-Cell Responses to Prevent Chronic Infection

T-cell responses are crucial for the control of viral infections, but the specific properties of antiviral T-cells required terminate viral replication and prevent establishment of chronic infections are poorly understood.  Nearly 170 million people worldwide are infected with HCV, and those who develop chronic HCV infection are at risk for chronic hepatitis, cirrhosis, liver failure, and/or hepatocellular carcinoma. Few effective treatments from chronic HCV are available, and a preventative vaccine does not exist. However, not everyone who is infected with HCV develops persistent infection, and ~20% of persons acutely infected clear the virus within 6 months. Current evidence suggests that HCV-specific T cell responses are a key factor in the outcome of acute HCV infection.  However, no clear immunological or virological differences have been identified which distinguish the T cell response in those who clear the virus from those who do not.  Moreover the molecular mechanisms underlying the differences in immune responses in cleared versus chronic HCV infection are poorly defined.  Better correlates of protective immunity are urgently needed to develop prophylactic vaccines and effective immunotherapies.  In this application we propose to:

1. Identify gene expression signatures in HCV specific T cells early during acute HCV infection that are associated with early control of HCV infection versus progression to chronic infection;

2. Use cross-species comparison of gene expression profiles from HCV infection and cleared versus chronic viral infection in mice to identify candidate mechanisms that underlie the generation and differentiation of virus-specific T cells capable of rapid viral control;

3. Use chemical genomic screens in primary human T cells to identify novel modulators of memory differentiation.

The significance of this proposal lies in its potential to establish correlates of protective T-cell immunity against HCV by gene expression profiling and to identify agents capable of modulating T-cells towards more effective differentiation states. Importantly, the findings could be directly translated into clinical applications. Establishing a validated signature that corresponds to the immune response required to control a chronic infection will allow the accelerated development of prophylactic and therapeutic vaccines and immunotherapies.

INVESTIGATOR BIOGRAPHIES

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W. Nicholas Haining, M.B., B.Ch.

Dr. Haining took his undergraduate and medical degrees at the Oxford University, before relocating to the US to complete his medical training in pediatric oncology at Children's Hospital, Boston, and Dana-Farber Cancer Institute.  He is currently an Assistant Professor of Pediatrics at Harvard Medical School, and holds joint clinical appointments at Children's Hospital, Boston, and Dana-Farber Cancer Institute in the Hematopoietic Stem Cell Transplant Program. 

Dr. Haining's laboratory is focussed on developing molecular predictors of T cell immunity, and discovering novel immunomodulatory drugs.  Using cross-species genomic analysis, his group has shown that memory differentiation in T and B cells employs a common transcriptional program.  He has gone on to show that this fundamental memory differentiation program is disrupted in dysfunctional T cells from chronic viral infection.  He is now applying this knowledge in two areas: 1) to develop gene-expression-based predictors of immune function that would help predict clinical outcome in chronic viral infection and cancer; and 2) to conduct high-throughput chemical genomic screens to identify modulators of memory differentiation.  Drugs identified in these screens would help boost the efficacy of vaccines and rescue defective immune responses.

Dr. Lauer has studied Medicine at the Universities of Tuebingen, Hamburg, and Bochum, Germany. He received his M.D. and Ph.D. from Ruhr-Universitaet Bochum, where he also trained in Internal Medicine and Gastroenterology. He relocated to the United States for a postdoctoral fellowship at the Partners AIDS Research Center at Massachusetts General Hospital and Harvard Medical School. He is now an Assistant Professor of Medicine at Harvard Medical School with a laboratory at the Gastrointestinal Unit at Massachusetts General Hospital.

Since his clinical training, Dr. Lauer has been interested in viral hepatitis, and this interest has continued into his research career studying viral immunology. His laboratory is focused on defining the immune correlates of protection from infection with Hepatitis B and hepatitis C by studying T-cell and natural killer cell responses specific for the viruses in subjects with acute, chronic, and resolved infection. The ultimate goal of these studies is to facilitate the design of prophylactic and therapeutic vaccines against these infections affecting hundreds of millions of people worldwide

Dr. Wherry received his undergraduate degree at Pennsylvania State University and Ph.D. at Thomas Jefferson University.  He then did postdoctoral training in the laboratory of Rafi Ahmed at Emory University.  He is currently an Assistant Professor in the Immunology Program and Wistar Vaccine Center at the Wistar Institute on the campus of the University of Pennsylvania in Philadelphia, PA.  Dr. Wherry also has an appointment in the Microbiology Department at the University of Pennsylvania. 

Dr. Wherry’s laboratory studies T cell responses to viral infections, with a strong emphasis on dissecting the molecular mechanisms underlying T cell dysfunction during chronic viral infections.  His work in this area using mouse models of chronic viral infection has demonstrated the hierarchical nature of T cell dysfunction, including defects in performing antiviral functions and defects in development of immunological memory.  He has also used genome-wide transcriptional profiling approaches to define the molecular features of this T cell dysfunction.  These studies have identified key molecular signatures of functional versus non-function T cell responses to viruses.  Ongoing work in the lab is examining pathways revealed by these approaches such as specific transcription factors and cell surface inhibitory receptors.  Understanding how to manipulate these pathways could provide novel approaches to therapeutic intervention during chronic viral infection.