PhD (Doctor of Philosophy)
Date of Award
Committee Chair or Co-Chairs
Jonathan P Moorman
David S. Chi, Jane E. Raulston, Michelle M. Duffourc, Robert V. Schoborg
In 1989 the hepatitis C virus was identified as a significant cause of post-transfusion hepatitis. Nearly two decades later there is still no vaccine, inadequate treatment options, and limited understanding of how the virus establishes chronicity in the majority of the people it infects. Recent reports suggest that the interaction of a negative co-stimulatory pathway mediated by PD-1 and PDL-1 is associated with persistent viral infection. The role, if any, that PD-1/PDL-1 has in HCV infection is unknown. In this study we report that PD-1 is upregulated in T-cells from persons with chronic HCV infection when compared to healthy donors. In addition, PD-1 and PDL-1 are upregulated on T-cells from healthy donors when exposed to extracellular HCV core protein (a nucleocapsid protein that is immunosuppressive); upregulation of PD-1 is mediated by core's ability to bind to the complement receptor gC1q. We also report that the observed T-cell function can be restored by blocking the PD-1/PDL-1 interaction. Our results indicate that HCV core can upregulate an important negative T-cell signaling pathway that is associated with viral persistence. This upregulation of PD-1/PDL-1 represents a novel and perhaps shared mechanism that viral pathogens may use to subvert the human immune response. It also represents a potential new treatment option for the millions of people who suffer from chronic hepatitis C infection.
Dissertation - Open Access
King, Billy Ellis, "T-cell Dysfunction by HCV Core Protein Involves PD-1/PD-L1 Signaling." (2007). Electronic Theses and Dissertations. Paper 2082. http://dc.etsu.edu/etd/2082
Copyright by the authors.