Cell-to-Cell Contact with Hepatitis C Virus-Infected Cells Reduces Functional Capacity of Natural Killer Cells

Abstract

The distinct feature of hepatitis C virus (HCV) infection is. On the other hand, inhibition of activating receptor expression on NK cell surfaces may also suppress NK cell responses (39). Because they are readily involved in the activation of resting NK cells (5), a reduced display of constitutively expressed activating receptors, such as NKG2D, NKp30, NKp46, DNAM-1, and 2B4, may dampen the functional capacity of NK cells to fight against viral infection. Cytokines secreted in response to HCMV infection indeed inhibit NKG2D expression on the surface of NK cells and limit the ability of NK cells to exert cytotoxicity against target cells (25).The prominent role of NK cells in the innate immune response to virus infection has prompted studies of the NK cell phenotype and functional properties in HCV infection. These include in vitro studies using HCV replicon systems, expression vectors encoding HCV proteins, and recombinant HCV proteins (9,12,24,35,36). For various reasons, these studies yielded contradictory results (12,24,35). It is difficult to interpret interaction between NK cells and HCV-infected cells in noninfectious models, which do not completely simulate the natural life cycle of HCV (19). Ex vivo studies using peripheral blood mononuclear cells (PBMCs) from patients with hepatitis C also showed discrepancies in the functional status of NK cells in HCV infection (1,11,15,26,27,30).Though small-animal models for immunologic research are not readily available yet, recently developed cell culture systems that generate infectious HCV virions in vitro provide more physiological settings in which to study interaction be-* Corresponding author. Mailing address:

Hepatitis C Virus–Infected Cells Downregulate NKp30 and Inhibit Ex Vivo NK Cell Functions

“…Our results, combined with previous studies indicating that HCV E2 molecules as displayed on HCV JFH1 virions do not inhibit NK cell functions (50), suggest that an HCV E2/NK CD81 interaction is not the primary cause of impaired NK cell functions mediated in vitro or in vivo by HCV-infected cells. Although HLA-E can be stabilized and upregulated by HCV core peptide (amino acids [35][36][37][38][39][40][41][42][43][44] and provides a ligand for inhibitory NK receptor NKG2A/CD94 (60), we and others did not observe increased expression of HLA-E on HCV-infected cells (52). Despite inhibition of ADCC, CD16 expression levels were also unaltered on NK cells exposed to HCV-infected cells.…”

“…Although this ligand may interact selectively with NKp30, disrupted signaling through this receptor could also affect z-chain-dependent signaling through CD16 to decrease ADCC. A previous study by Yoon et al (52) showed that NK cytotoxicity and IFN-g production was reduced following an 18 h coculture with HCV-infected cells and noted a decline in NKp30 and NKG2D expression on NK cells. We did not observe a reduction in NKG2D expression on NK cells after a 5 h incubation with infected cells.…”

Hepatitis C Virus Impairs Natural Killer Cell-Mediated Augmentation of Complement Synthesis

“…HCV affects NK cell activity through direct cell-to-cell interaction via CD81 or NK cell receptors or in an indirect manner via cytokine or TRAIL release (6)(7)(8)(9). HCV E2 glycoprotein is suggested to inhibit NK cells directly by cross-linking CD81 (6,10).…”

IL-26 is overexpressed in chronically HCV-infected patients and enhances TRAIL-mediated cytotoxicity and interferon production by human NK cells

“…Interestingly, NK cells, which represent 30%–50% of intrahepatic lymphocytes (compared with 5%–15% in the periphery), are involved in every stage of HCV infection (from spontaneous clearance in the acute infection, to treatment-induced HCV clearance) 6 8. They kill HCV-infected hepatoma cells through the release of the cytotoxic molecules perforin and granzyme and through surface expression of tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) 7 9. IFN-α-stimulated NK cells express TRAIL and kill HCV-infected hepatoma cells via TRAIL 7.…”