Hepatitis C virions subvert natural killer cell activation to generate a cytokine environment permissive for infection
Received 15 July 2009; received in revised form 15 September 2009; accepted 26 September 2009. published online 19 November 2009.
Background & Aims
Hepatitis C virus (HCV) is remarkably successful in establishing persistent infections due to its ability to evade host immune responses through a combination of mechanisms including modulation of interferon (IFN) signalling in infected cells, interference with effector cell function of the immune system and continual viral genetic variation. We have previously demonstrated that natural killer (NK) cells can be inhibited in vitro by recombinant HCV glycoprotein E2 via cross-linking of CD81, a cellular co-receptor for the virus.
Methods
Taking advantage of the recently established tissue-culture system for HCV, we have studied the effects of CD81 engagement by the HCV envelope glycoprotein E2 when the protein is part of complete, infectious viral particles. Specifically, we asked whether exposure to HCV viral particles (HCVcc) affects activation of NK cells and whether altered NK cell activation, in turn, impacts on HCV infectivity.
Results
We found that immobilized HCVcc, unlike soluble HCVcc, inhibited IFN-γ production by interleukin (IL)-12 activated NK cells, and that this effect was mediated by engagement of cellular CD81 by HCV-virion displayed E2. In contrast, NK-production of IL-8 was increased in the presence of HCV. The cytokines produced by IL-12 activated NK cells strongly reduced the establishment of productive HCV infection. Importantly, NK-cell derived cytokines secreted in the presence of HCVcc showed a diminished antiviral effect that correlated with IFN-γ reduction, while IL-8 concentrations had no impact on HCV infectivity.
Conclusions
Exposure to HCVcc modulates the pattern of cytokines produced by NK cells, leading to reduced antiviral activity.
1Department of Microbial Molecular Biology, Novartis Vaccines and Diagnostics, via Fiorentina 1, 53100 Siena, Italy
2Department of Immunology, Novartis Vaccines and Diagnostics, via Fiorentina 1, 53100 Siena, Italy
3Department of Immunology, Novartis Vaccines and Diagnostics, 45 Sidney Street, Cambridge, MA 02139, USA
Corresponding author. Present address: Division of Immunoregulation, National Institute for Medical Research, The Ridgeway, Mill Hill, NW7 1AA London, UK. Tel.: +44 02089593666x2260.
† Present address: Division of Immunoregulation, National Institute for Medical Research, The Ridgeway, Mill Hill, NW7 1AA London, UK.
ABSTRACT