PD-1 and HCV

[veritas]

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19247441

From the summary:

"Hepatitis C virus (HCV) is an important human pathogen with a high rate of persistence associated with chronic liver disease that can progress to cirrhosis and hepatocellular carcinoma. Chronic HCV infection occurs in the setting of impaired antiviral T cells that over-express an inhibitory receptor PD-1 (programmed death-1 receptor). Recent studies showed that in vitro inhibition of the PD-1 pathway via an inhibitory antibody can reverse the functional impairment in HCV-specific CD8 T cells from blood but not the liver (the site of viral infection and disease progression). In this study, we show that a second co-inhibitory receptor, CTLA-4, is upregulated in HCV-specific CD8 T cells from the liver and that combined PD-1/CTLA-4 blockade (but not single blockade of PD-1 or CTLA-4) can synergistically enhance their function. This functional enhancement was CD28-dependent but CD4-independent. This effect also differed between viruses, tissue compartments (liver vs. periphery) and clinical status (acute vs. chronic). We conclude that PD-1, CTLA-4, and CD28 expression profiles define a novel hierarchy in HCV-specific CD8 T cell exhaustion than can be synergistically reversed by combined inhibitory receptor blockade. These findings have potential immunotherapeutic applications, provided that no autoimmunity is induced."