Decoding the complexity of type I interferon to treat persistent viral infections

•Type I interferons (IFN-I) underlie many of the immune dysfunctions associated with persistent virus infection.•IFN-I simultaneously have critical antiviral and immunomodulatory functions during viral persistence.•Blocking IFN-I in a mouse model enhanced the immune response to control persistent virus infection.•Therapeutically interfering with IFN-I signaling could help treat multiple disease states.

Type I interferons (IFN-I) are a broad family of cytokines that are central to the innate immune response. These proteins have long been appreciated for the critical roles they play in restraining viral infections and shaping antiviral immune responses. However, in recent years there has been increased awareness of the immunosuppressive actions of these proteins as well. Although there are many current therapeutic applications to manipulate IFN-I pathways, we have limited understanding of the mechanisms by which these therapies are actually functioning. In this review, we highlight the diversity and temporal impact of IFN-I signaling, discuss the current therapeutic uses of IFN-I, and explore the strategy of blocking IFN-I to alleviate immune dysfunction in persistent virus infections.