Hepatitis C virus (HCV) infects 185 million persons worldwide, is the leading indication for liver transplantation and, in the US, has a higher mortaliy rate than HIV. The annual healthcare costs associated with HCV exceed $9 billion, a number expected to increase as the epidemic matures and end stage liver disease peaks over the next decade. By virtue of its remarkable predilection for persistence, HCV is a model chronic viral infection. Mounting evidence supports the idea that HCV, while inducing type I IFN expression, maintains chronicity by virtue of global suppression of host innate and adaptive immunity. The mainstay of treatment for the last two decades, IFN-?-based regimens are ineffective in many patient subgroups and have significant side effects. The recent development of highly effective direct acting antivirals (DAA) against HCV promises to alter the landscape of this devastating infection by offering curative therapy without IFN. However, it remains essential that we understand what type of immunity remains following pharmacological eradication of the virus because: a) many HCV infected subjects remain at risk for re-infection;and b) DAAs are only partially effective in some patient subgroups, particularly those with past treatment with IFN. The imminent availability of IFN-free treatment for HCV offers an unprecedented opportunity to understand broad questions about alterations in immunity in humans with cure of chronic infections. Until now, mechanistic dissection of human immune responses has been challenging due to limited ability to directly perturb the system. The organizing principle of this U19 Program therefore, is to capitalize on the unique opportunity to, for the first time, cure chronic viral infection in humans without immune modulation and interrogate the immunological changes that ensue. Thus, we have formulated the following central hypothesis for this Program: DAA-mediated cure of chronic HCV infection will lead to partial """"""""resetting"""""""" of some immune abnormalities, but specific immunological defects will persist in some subjects that prevent development of optimal immunity to HCV. We will test this hypothesis through a set of integrated Projects and Cores.

Public Health Relevance

There are 185 million people worldwide chronically infected with HCV and this infection is a major cause of liver failure and liver cancer with annual health care costs of ~$9 billion in the US. New antiviral drugs will have a major impact, but many patients are at risk for re-infection. Thus, it is imperative that we understand what type of immunity persists following cure of HCV infection to not only determine whether drug cured subjects have immunity but also to further understand immunity to chronic infections in general.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-LAR-I (J1))
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Quill, Helen R
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Massachusetts General Hospital
United States
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Stelekati, Erietta; Chen, Zeyu; Manne, Sasikanth et al. (2018) Long-Term Persistence of Exhausted CD8 T Cells in Chronic Infection Is Regulated by MicroRNA-155. Cell Rep 23:2142-2156
Kurioka, Ayako; van Wilgenburg, Bonnie; Javan, Reza Rezaei et al. (2018) Diverse Streptococcus pneumoniae Strains Drive a Mucosal-Associated Invariant T-Cell Response Through Major Histocompatibility Complex class I-Related Molecule-Dependent and Cytokine-Driven Pathways. J Infect Dis 217:988-999
Qu, Chen; Zheng, Dandan; Li, Sai et al. (2018) Tyrosine kinase SYK is a potential therapeutic target for liver fibrosis. Hepatology :
Yu, Wen-Han; Cosgrove, Cormac; Berger, Christoph T et al. (2018) ADCC-Mediated CD56DIM NK Cell Responses Are Associated with Early HBsAg Clearance in Acute HBV Infection. Pathog Immun 3:2-18
Johnson, John L; Georgakilas, Georgios; Petrovic, Jelena et al. (2018) Lineage-Determining Transcription Factor TCF-1 Initiates the Epigenetic Identity of T Cells. Immunity 48:243-257.e10
Gordon, Claire L; Hutchings, Claire L; Highton, Andrew J et al. (2018) Memory inflation following adenoviral vaccination depends on IL-21. Vaccine 36:7011-7016
Carty, Shannon A; Gohil, Mercy; Banks, Lauren B et al. (2018) The Loss of TET2 Promotes CD8+ T Cell Memory Differentiation. J Immunol 200:82-91
Gordon, Claire Louse; Lee, Lian Ni; Swadling, Leo et al. (2018) Induction and Maintenance of CX3CR1-Intermediate Peripheral Memory CD8+ T Cells by Persistent Viruses and Vaccines. Cell Rep 23:768-782
Duan, Xiaoqiong; Li, Shilin; Holmes, Jacinta A et al. (2018) MicroRNA 130a Regulates both Hepatitis C Virus and Hepatitis B Virus Replication through a Central Metabolic Pathway. J Virol 92:
Bengsch, Bertram; Ohtani, Takuya; Khan, Omar et al. (2018) Epigenomic-Guided Mass Cytometry Profiling Reveals Disease-Specific Features of Exhausted CD8 T Cells. Immunity 48:1029-1045.e5

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