Persistent viral infections are among the greatest health concerns worldwide. By definition, immune escape is required for viral persistence, and many of the suppressive factors involved are being identified. Yet, it is still unclear how prolonged virus replication leads to the expression of the many and mechanistically diverse suppressive factors, pathways and cells that inhibit immunity during persistent viral infections. Type I interferons (IFN-I) are well known for their antiviral activity during virus infection. However, using the lymphocytic choriomeningitis virus (LCMV) system, we discovered that in addition to their critical antiviral role throughout viral persistence, sustained IFN-I production ed to many of the suppressive mechanisms and immune dysfunctions associated with persistent viral infections. Antibody blockade of IFN-I signaling decreased immunosuppression, restored immune competence and facilitated immune mediated control of the persistent infection. In the current proposal, we will mechanistically define how IFN-I functions as the mediator of the multiple and diverse parameters of immunosuppression that ultimately potentiate viral persistence. We will then test the hypothesis that the distinct antiviral and suppressive aspects of IFN-I signaling can be uncoupled to specifically inhibit the negative while maintaining the critical positive functions of IFN-I to restore immunity and control infection. These studies will provide critical biologic insight into how IFN-I simultaneously induces antiviral and suppressive functions and will potentially guide the way we therapeutically target IFN-I to treat disease. Finally, we will investigate a novel IFN-I induced mechanism of immunosuppression to define how IFN-I implements secondary down-stream effectors to promote viral persistence. Ultimately, our study will provide fundamental insight into a new aspect of IFN-I biology and facilitate the first understanding of a newly described mechanism of immunosuppression potentiating viral persistence.
Therapies to treat many persistent virus infections are needed. The experiments outlined in this proposal will investigate a newly defined mechanism of immunosuppression that facilitates persistent viral infection. Ultimately, identification of the mechanisms that undermine immunity will aid in the design of restorative therapies to amplify the immune response to control persistent viral infections.
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