Research Article: Hepatitis C virus infection inhibits a Src-kinase regulatory phosphatase and reduces T cell activation in vivo

Date Published: February 24, 2017

Publisher: Public Library of Science

Author(s): Nirjal Bhattarai, James H. McLinden, Jinhua Xiang, M. Meleah Mathahs, Warren N. Schmidt, Thomas M. Kaufman, Jack T. Stapleton, Timothy L. Tellinghuisen.

http://doi.org/10.1371/journal.ppat.1006232

Abstract

Among human RNA viruses, hepatitis C virus (HCV) is unusual in that it causes persistent infection in the majority of infected people. To establish persistence, HCV evades host innate and adaptive immune responses by multiple mechanisms. Recent studies identified virus genome-derived small RNAs (vsRNAs) in HCV-infected cells; however, their biological significance during human HCV infection is unknown. One such vsRNA arising from the hepatitis C virus (HCV) E2 coding region impairs T cell receptor (TCR) signaling by reducing expression of a Src-kinase regulatory phosphatase (PTPRE) in vitro. Since TCR signaling is a critical first step in T cell activation, differentiation, and effector function, its inhibition may contribute towards HCV persistence in vivo. The effect of HCV infection on PTPRE expression in vivo has not been examined. Here, we found that PTPRE levels were significantly reduced in liver tissue and peripheral blood mononuclear cells (PBMCs) obtained from HCV-infected humans compared to uninfected controls. Loss of PTPRE expression impaired antigen-specific TCR signaling, and curative HCV therapy restored PTPRE expression in PBMCs; restoring antigen-specific TCR signaling defects. The extent of PTPRE expression correlated with the amount of sequence complementarity between the HCV E2 vsRNA and the PTPRE 3’ UTR target sites. Transfection of a hepatocyte cell line with full-length HCV RNA or with synthetic HCV vsRNA duplexes inhibited PTPRE expression, recapitulating the in vivo observation. Together, these data demonstrate that HCV infection reduces PTPRE expression in the liver and PBMCs of infected humans, and suggest that the HCV E2 vsRNA is a novel viral factor that may contribute towards viral persistence.

Partial Text

Hepatitis C virus (HCV) persistently infects more than 120 million people globally, and chronic viremia frequently leads to cirrhosis and hepatocellular carcinoma [1–8]. Although numerous factors appear to contribute to viral persistence, the mechanisms by which HCV evades immune responses are incompletely understood. Prior studies found that HCV-infection is associated with reduced T cell function in vitro, impaired HCV-specific intrahepatic and peripheral T cell response ex vivo, delayed onset of HCV-specific humoral and cellular immunity in vivo, and impaired immune responses to HBV and adenoviral vaccination [2, 8–20].

Virus derived small RNAs (vsRNAs) encoded by DNA viruses and retroviruses play an important role in viral replication and may contribute to immune evasion [26, 27]. Although vsRNAs are found in cells infected with cytoplasmic RNA viruses in vitro [11, 31–35, 57, 58], their role in human infection is not characterized, and their significance is debated [28, 30]. HCV is unusual among cytoplasmic RNA viruses in that it establishes persistent infection in the majority of infected people [2, 59]. Previous studies found that HCV infection impairs T cell function, and presumably this contributes to viral persistence [7–11, 59].

 

Source:

http://doi.org/10.1371/journal.ppat.1006232

 

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