We have recently shown that the killer cell immunoglobulin-like receptors (KIR) in combination with cognate MHC class I ligands determine the outcome of HCV infection. The goal of this project is to understand the mechanisms by which these interactions are protective.
Specific Aim 1 studies KIR and MHC class I genetics to determine if this protection is present in the context of known doses and genotypes of HCV infection. Analysis of the presence or absence of specific KIR and MHC genes will be performed in individuals having received known inocula of HCV. Correlations of receptor-ligand combinations with the outcome of HCV infection will be sought.
Specific Aim 2 tests the hypothesis that successful resolution of HCV infection is dependent on the strength of the KIR:MHC class I binding interaction. We will use cellular binding and flow cytometry assays to compare KIR binding to MHC class l-positive targets derived from individuals either clearing HCV infection or remaining persistently infected.
Specific Aim 3 is a longitudinal analysis of NK cells in acute HCV infection in individuals undergoing self-limiting HCV infection, chronic HCV infection, a successful memory response and an unsuccessful memory response. The presence of NK cells with protective phenotypes will be sought by flow cytometry and real-time PCR analysis. These analyses will be combined with T cell analyses performed by Dr C Walker and Dr S Kalams to give an integrated picture of a successful and unsuccessful immune response to HCV. Hepatitis C virus affects 170 million individuals worldwide. Understanding how natural killer cells and their receptors assist in resolving acute HCV infection could lead to the generation of novel NK cell based therapies for individuals chronically infected with hepatitis C virus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI048231-07
Application #
7310180
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
7
Fiscal Year
2006
Total Cost
$236,387
Indirect Cost
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
Fuller, Michael J; Callendret, Benoit; Zhu, Baogong et al. (2013) Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1). Proc Natl Acad Sci U S A 110:15001-6
Lanford, Robert E; Feng, Zongdi; Chavez, Deborah et al. (2011) Acute hepatitis A virus infection is associated with a limited type I interferon response and persistence of intrahepatic viral RNA. Proc Natl Acad Sci U S A 108:11223-8
Tanwar, Sudeep; Khakoo, Salim (2009) What to do if standard therapy for hepatitis C fails. F1000 Med Rep 1:41
Bowen, David G; Shoukry, Naglaa H; Grakoui, Arash et al. (2008) Variable patterns of programmed death-1 expression on fully functional memory T cells after spontaneous resolution of hepatitis C virus infection. J Virol 82:5109-14
Uebelhoer, Luke; Han, Jin-Hwan; Callendret, Benoit et al. (2008) Stable cytotoxic T cell escape mutation in hepatitis C virus is linked to maintenance of viral fitness. PLoS Pathog 4:e1000143
Ramalingam, Ramesh K; Meyer-Olson, Dirk; Shoukry, Naglaa H et al. (2008) Kinetic analysis by real-time PCR of hepatitis C virus (HCV)-specific T cells in peripheral blood and liver after challenge with HCV. J Virol 82:10487-92
Bowen, David G; Walker, Christopher M (2005) Mutational escape from CD8+ T cell immunity: HCV evolution, from chimpanzees to man. J Exp Med 201:1709-14
Kimura, Yoichi; Gushima, Toshifumi; Rawale, Sharad et al. (2005) Escape mutations alter proteasome processing of major histocompatibility complex class I-restricted epitopes in persistent hepatitis C virus infection. J Virol 79:4870-6
Bowen, David G; Walker, Christopher M (2005) The origin of quasispecies: cause or consequence of chronic hepatitis C viral infection? J Hepatol 42:408-17
Elkington, Rebecca; Shoukry, Naglaa H; Walker, Susan et al. (2004) Cross-reactive recognition of human and primate cytomegalovirus sequences by human CD4 cytotoxic T lymphocytes specific for glycoprotein B and H. Eur J Immunol 34:3216-26

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