Negative Regulation of Type I IFN Expression by OASL1 Permits Chronic Viral Infection and CD8+ T-Cell Exhaustion

The type i interferons (ifn-is) are critical not only in early viral control but also in prolonged t-cell immune responses. however,chronic viral infections such as those of human immunodeficiency virus (hiv) and hepatitis c virus (hcv) in humans and lymphocytic choriomeningitis virus (lcmv) in mice overcome this early ifn-i barrier and induce viral persistence and exhaustion of t-cell function. although various t-cell-intrinsic and -extrinsic factors are known to contribute to induction of chronic conditions,the roles of ifn-i negative regulators in chronic viral infections have been largely unexplored. herein,we explored whether 2′-5′ oligoadenylate synthetase-like 1 (oasl1),a recently defined ifn-i negative regulator,plays a key role in the virus-specific t-cell response and viral defense against chronic lcmv. to this end,we infected oasl1 knockout and wild-type mice with lcmv cl-13 (a chronic virus) and monitored t-cell responses,serum cytokine levels,and viral titers. lcmv cl-13-infected oasl1 ko mice displayed a sustained level of serum ifn-i,which was primarily produced by splenic plasmacytoid dendritic cells,during the very early phase of infection (2-3 days post-infection). oasl1 deficiency also led to the accelerated elimination of viremia and induction of a functional antiviral cd8 t-cell response,which critically depended on ifn-i receptor signaling. together,these results demonstrate that oasl1-mediated negative regulation of ifn-i production at an early phase of infection permits viral persistence and suppresses t-cell function,suggesting that ifn-i negative regulators,including oasl1,could be exciting new targets for preventing chronic viral infection. © 2013 lee et al.