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Hepatitis C virus infection inhibits a Src-kinase regulatory phosphatase and reduces T cell activation in vivo
Journal article   Open access   Peer reviewed

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

Nirjal Bhattarai, James H McLinden, Jinhua Xiang, M. Meleah Mathahs, Warren N Schmidt, Thomas M Kaufman and Jack T Stapleton
PLoS pathogens, Vol.13(2), pp.e1006232-e1006232
02/01/2017
DOI: 10.1371/journal.ppat.1006232
PMCID: PMC5342304
PMID: 28235043
url
https://doi.org/10.1371/journal.ppat.1006232View
Published (Version of record) Open Access

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. The mechanism by which hepatitis C virus (HCV) establishes persistent human infection is complex and incompletely understood. Recent studies identified virus-derived small RNAs (vsRNAs) in HCV-infected cells; however, their biological significance is unclear. One HCV vsRNA arising from the E2 coding region reduces expression of a Src-kinase regulatory phosphtase (PTPRE) both in hepatocytes and lymphocytes in vitro , and leads to impaired T cell function. Here, we show that PTPRE expression is reduced in liver tissues and peripheral blood mononuclear cells (PBMCs) obtained from HCV-infected humans. Furthermore, serum from HCV infected individuals reduced antigen-specific TCR signaling, and curative anti-HCV therapy restored PTPRE expression in HCV-infected humans coincident to rescuing antigen-specific TCR-signaling defects. Transfection of a hepatocyte cell line with HCV genomic RNA or synthetic vsRNA duplexes inhibited PTPRE expression, recapitulating the in vivo observations. Together, these data suggest that HCV genomic RNA is processed into short, regulatory HCV RNA sequences that regulate PTPRE levels in HCV-infected humans, contributing to HCV immune evasion in vivo .
 Biology and life sciences Medicine and health sciences Research and Analysis Methods

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