New insights into type I interferon and the immunopathogenesis of persistent viral infections

Most viruses generate potent T cell responses that rapidly control infection. However, certain viruses can subvert the immune response to establish persistent infections. The inability to clear virus induces an immunosuppressive program leading to the sustained expression of many immunoregulatory molecules that down-regulate T cell responses. Further, viral persistence is associated with multiple immune dysfunctions including lymphoid disorganization, defective antigen presentation, aberrant B cell responses and hypergammaglobulinemia. Although best known for its antiviral activity, recent data has highlighted the role of type I IFN (IFN-I) signaling as a central mediator of immunosuppression during viral persistence. It is also becoming increasingly apparent that many of the immune dysfunctions during persistent virus infection can be attributed directly or indirectly to the effects of chronic IFN-I signaling. This review explores the increasingly complex role of IFN-I in the regulation of immunity against persistently replicating virus infections and examines current and potential uses of IFN-I and blockade of IFN-I signaling to dampen chronic inflammation and activation in the clinic.