Hepatitis C virus (HCV) infection resolves spontaneously in humans and chimpanzees with strong, sustained cellular immune responses. During the last funding period we documented long-lived CD4+ and CD8+ memory T cells in immune chimpanzees that were required for rapid control of a second virus infection. Why T cell immunity fails during chronic infection is still not understood and is the major focus of this proposal. Mutational escape of most MHC class I epitopes was observed in viruses from persistently infected chimpanzees but this is probably not the only mechanism of CD8+ T cell evasion. Preliminary data indicate that some HCV-specific CD8+ T cells make the anti-inflammatory cytokine IL-10 instead of IFN-gamma during persistent infection.
In Specific Aim 1 we will investigate the hypothesis that IL-10 inducing epitopes are not under immune selection pressure because this skewed cytokine response facilitates virus persistence.
Specific Aim 2 proposes direct visualization of CD8+ T cells in the persistently infected liver with MHC class I tetramers to determine if ineffective virus control is associated with an immature phenotype and/or lack of effector molecules like perforin.
In Specific Aim 3 we will use MHC class II tetramer technology to determine if CD4+ T cells are also compartmentalized to the liver but lack adequate helper activity for HCV clearance, perhaps because of mutations that alter epitope recognition. Finally, the antiviral function of CD4+ and CD8+ T cells in persistently infected animals will be tested directly by superinfection with wild-type HCV (Specific Aim 4). Our four specific aims are to:
Specific Aim 1. Map MHC class I epitopes targeted by IL-10 or IFN-gamma producing CD8+ T cells and compare their susceptibility to immune selection pressure.
Specific Aim 2 Determine if CD8+ T cells in liver have an immature phenotype that predicts a lack of in vivo effector function.
Specific Aim 3. Define the repertoire and frequency of HCV-specific CD4+ T cells in the liver of individuals with persistent and resolved infections.
Specific Aim 4. Superinfect persistently viremic chimpanzees with wild-type HCV to test directly the in situ responsiveness of CD4+ and CD8+ T cells.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (ZRG1-IHD (01))
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Koshy, Rajen
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Nationwide Children's Hospital
United States
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Mitchell, Jonathan K; Midkiff, Bentley R; Israelow, Benjamin et al. (2017) Hepatitis C Virus Indirectly Disrupts DNA Damage-Induced p53 Responses by Activating Protein Kinase R. MBio 8:
Lanford, Robert E; Walker, Christopher M; Lemon, Stanley M (2017) The Chimpanzee Model of Viral Hepatitis: Advances in Understanding the Immune Response and Treatment of Viral Hepatitis. ILAR J 58:172-189
Walker, Christopher M (2017) Designing an HCV vaccine: a unique convergence of prevention and therapy? Curr Opin Virol 23:113-119
Walker, Christopher M; Lemon, Stanley M (2016) Getting the Skinny on CD4(+) T Cell Survival in Fatty Livers. Immunity 44:725-7
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Ploss, Alexander; Walker, Christopher (2015) Editorial overview: Progress and challenges in modeling human viral diseases in vivo. Curr Opin Virol 13:v-vii
Walker, Christopher M; Grakoui, Arash (2015) Hepatitis C virus: why do we need a vaccine to prevent a curable persistent infection? Curr Opin Immunol 35:137-43
Callendret, Benoit; Eccleston, Heather B; Hall, Shelby et al. (2014) T-cell immunity and hepatitis C virus reinfection after cure of chronic hepatitis C with an interferon-free antiviral regimen in a chimpanzee. Hepatology 60:1531-40

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