Hepatitis C virus (HCV) establishes chronic infection in the liver of nearly 80% of those infected and in addition to causing hepatitis, may cause liver cirrhosis and hepatocellular carcinoma. These detrimental long-term sequelae of persistent HCV infection now comprise the leading indication for liver transplantation in the United States. Defining the elements of the immune response that fail or are insufficient to mediate HCV clearance or resolution in the majority of those infected is critical for advancing our understanding of how to therapeutically intervene in HCV disease pathogenesis. We recently published work utilizing the chimpanzee experimental model that established for the first time the fundamental importance of the CD4+ T helper cell in HCV infection resolution: in chimpanzees that had previously resolved infection with HCV, experimental depletion of the CD4+ T cell compartment prior to re-infection with HCV resulted in the emergence of viral escape mutations, the inability to eliminate viremia and the establishment of chronic HCV infection. Accordingly, we now postulate that in the natural course of HCV infection, viral persistence is a direct result of the inadequacy of the CD4+ T cell compartment. Specifically, we hypothesize that the interaction between CD4+ T cells and professional antigen presenting cells (APCs) is insufficient in HCV infected individuals, and that the resultant failure to generate and maintain a robust CD4+ T helper response contributes to viral persistence. The work proposed here is based both on our work in the chimpanzee model and on observations in human patients. The experimental focus of this proposal is on defining the mechanisms by which T cells fail in persistent HCV infection. ? ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Virology - B Study Section (VIRB)
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Koshy, Rajen
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Emory University
Internal Medicine/Medicine
Schools of Medicine
United States
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Tedesco, Dana; Thapa, Manoj; Chin, Chui Yoke et al. (2018) Alterations in Intestinal Microbiota Lead to Production of Interleukin 17 by Intrahepatic ?? T-Cell Receptor-Positive Cells and Pathogenesis of Cholestatic Liver Disease. Gastroenterology 154:2178-2193
Tedesco, Dana; Grakoui, Arash (2018) Environmental peer pressure: CD4+ T cell help in tolerance and transplantation. Liver Transpl 24:89-97
Aguilar-Valenzuela, Renan; Netland, Jason; Seo, Young-Jin et al. (2018) Dynamics of Tissue-Specific CD8+ T Cell Responses during West Nile Virus Infection. J Virol 92:
Tedesco, Dana; Thapa, Manoj; Gumber, Sanjeev et al. (2017) CD4+ Foxp3+ T cells promote aberrant immunoglobulin G production and maintain CD8+ T-cell suppression during chronic liver disease. Hepatology 65:661-677
Honegger, Jonathan R; Tedesco, Dana; Kohout, Jennifer A et al. (2016) Influence of IFNL3 and HLA-DPB1 genotype on postpartum control of hepatitis C virus replication and T-cell recovery. Proc Natl Acad Sci U S A 113:10684-9
Price, Aryn A; Tedesco, Dana; Prasad, Mona R et al. (2016) Prolonged activation of innate antiviral gene signature after childbirth is determined by IFNL3 genotype. Proc Natl Acad Sci U S A 113:10678-83
Moradpour, Darius; Grakoui, Arash; Manns, Michael P (2016) Future landscape of hepatitis C research - Basic, translational and clinical perspectives. J Hepatol 65:S143-S155
Seo, Young-Jin; Jothikumar, Prithiviraj; Suthar, Mehul S et al. (2016) Local Cellular and Cytokine Cues in the Spleen Regulate In Situ T Cell Receptor Affinity, Function, and Fate of CD8+ T Cells. Immunity 45:988-998
Boisvert, Maude; Zhang, Wanrui; Elrod, Elizabeth J et al. (2016) Novel E2 Glycoprotein Tetramer Detects Hepatitis C Virus-Specific Memory B Cells. J Immunol 197:4848-4858
Grakoui, Arash; Crispe, Ian Nicholas (2016) Presentation of hepatocellular antigens. Cell Mol Immunol 13:293-300

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