Hepatitis C virus (HCV) evades NKG2D-dependent NK cell responses through NS5A-mediated imbalance of inflammatory cytokines

Understanding how hepatitis c virus (hcv) induces and circumvents the host's natural killer (nk) cell-mediated immunity is of critical importance in efforts to design effective therapeutics. we report here the decreased expression of the nkg2d activating receptor as a novel strategy adopted by hcv to evade nk-cell mediated responses. we show that chronic hcv infection is associated with expression of ligands for nkg2d,the mhc class i-related chain (mic) molecules,on hepatocytes. however,nkg2d expression is downmodulated on circulating nk cells,and consequently nk cell-mediated cytotoxic capacity and interferon-γ production are impaired. using an endotoxin-free recombinant ns5a protein,we show that ns5a stimulation of monocytes through toll-like receptor 4 (tlr4) promotes p38- and pi3 kinase-dependent il-10 production,while inhibiting il-12 production. in turn,il-10 triggers secretion of tgfβ which downmodulates nkg2d expression on nk cells,leading to their impaired effector functions. moreover,culture supernatants of hcv jfh1 replicating huh-7.5.1 cells reproduce the effect of recombinant ns5a on nkg2d downmodulation. exogenous il-15 can antagonize the tgfβ effect and restore normal nkg2d expression on nk cells. we conclude that nkg2d-dependent nk cell functions are modulated during chronic hcv infection,and demonstrate that this alteration can be prevented by exogenous il-15,which could represent a meaningful adjuvant for therapeutic intervention. © 2010 séne et al.