Hepatitis C virus (HCV) is the most common cause of chronic viral hepatitis in the United States, and is a significant cause of morbidity and mortality. The T cell response directed at HCV derived antigens is thought to be important in the pathogenesis of HCV mediated disease, participating in favorable clinical outcome as well as in organ damage. Effector dysfunction of HCV reactive T cells has been proposed to contribute to the common persistence of HCV infection. In fact, HCV infection has been proposed to result in ARC dysfunction, abnormal APC-T cell interactions, and for the presence of dysfunctional virus specific T cells. Peripherally circulating immature dendritic cell (DC) subpopulations (MDC and PDC or myeloid and plasmacytoid DC) have emerged as key APC in shaping T cell immunity. Dysfunction in expanded MDC has been shown in HCV infection. An improved understanding of MDC and PDC function, and T cell responsiveness, during HCV infection may reveal important insight into host defense mechanisms, and lay the foundation for appropriate design of therapeutics in HCV infection. We will investigate the hypothesis that HCV infection results in altered DC ability to undergo maturation, manifesting in an impaired ability to process and present antigen, and a deficit in secretion of immune regulatory cytokines, and impaired activation of naive and effector memory T cell immunity that in turn prevents control of the infection. In addition HCV infection may affect T-cell responsiveness to normal functioning DC. To test this hypothesis we will determine the impact of HCV infection on DC phenotype and function, the impact of HCV on T cells by characterizing T cell responsiveness in HCV infected and healthy control subjects, and the effects of HCV core protein as a direct inhibitor DC function. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK068361-01A2
Application #
7032816
Study Section
Special Emphasis Panel (ZRG1-IHD (01))
Program Officer
Doo, Edward
Project Start
2006-04-01
Project End
2011-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
1
Fiscal Year
2006
Total Cost
$253,380
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Reyes-Avilés, Elane; Kostadinova, Lenche; Rusterholtz, Anne et al. (2015) Presence of Rheumatoid Factor during Chronic HCV Infection Is Associated with Expansion of Mature Activated Memory B-Cells that Are Hypo-Responsive to B-Cell Receptor Stimulation and Persist during the Early Stage of IFN Free Therapy. PLoS One 10:e0144629
Judge, Chelsey J; Reyes-Aviles, Elane; Conry, Sara J et al. (2015) HBD-3 induces NK cell activation, IFN-? secretion and mDC dependent cytolytic function. Cell Immunol 297:61-8
Meng, Qinglai; Rani, M R Sandhya; Sugalski, Julia M et al. (2014) Natural cytotoxicity receptor-dependent natural killer cytolytic activity directed at hepatitis C Virus (HCV) is associated with liver inflammation, African American race, IL28B genotype, and response to pegylated interferon/ribavirin therapy in chronic H J Infect Dis 209:1591-601
Kambara, Hiroto; Niazi, Farshad; Kostadinova, Lenche et al. (2014) Negative regulation of the interferon response by an interferon-induced long non-coding RNA. Nucleic Acids Res 42:10668-80
Schlatzer, Daniela M; Sugalski, Julia M; Chen, Yanwen et al. (2013) Plasma proteome analysis reveals overlapping, yet distinct mechanisms of immune activation in chronic HCV and HIV infections. J Acquir Immune Defic Syndr 63:563-71
Leeansyah, Edwin; Malone, David F G; Anthony, Donald D et al. (2013) Soluble biomarkers of HIV transmission, disease progression and comorbidities. Curr Opin HIV AIDS 8:117-24
Conry, Sara J; Meng, Qinglai; Hardy, Gareth et al. (2012) Genetically associated CD16(+)56(-) natural killer cell interferon (IFN)-?R expression regulates signaling and is implicated in IFN-?-induced hepatitis C virus decline. J Infect Dis 205:1131-41
Anthony, Donald D; Conry, Sara J; Medvik, Kathy et al. (2012) Baseline levels of soluble CD14 and CD16+56- natural killer cells are negatively associated with response to interferon/ribavirin therapy during HCV-HIV-1 coinfection. J Infect Dis 206:969-73
Schlatzer, Daniela M; Sugalski, Julia; Dazard, Jean-Eudes et al. (2012) A quantitative proteomic approach for detecting protein profiles of activated human myeloid dendritic cells. J Immunol Methods 375:39-45
Yonkers, Nicole L; Rodriguez, Benigno; Asaad, Robert et al. (2011) Systemic immune activation in HIV infection is associated with decreased MDC responsiveness to TLR ligand and inability to activate naive CD4 T-cells. PLoS One 6:e23884

Showing the most recent 10 out of 18 publications