Abstract
Type I interferons (IFN-I) are one of the primary immune defenses against viruses. Similar to all other molecular mechanisms that are central to eliciting protective immune responses, IFN-I expression is subject to homeostatic controls that regulate cytokine levels upon clearing the infection. However, in the case of established persistent viral infection, sustained elevation of IFN-I expression bears deleterious effects to the host and is today considered as the major driver of inflammation and immunosuppression. In fact, numerous emerging studies place sustained IFN-I expression as a common nexus in the pathogenesis of multiple chronic diseases including persistent infections with the human immunodeficiency virus type 1 (HIV-1), simian immunodeficiency virus (SIV), as well as the rodent-borne lymphocytic choriomeningitis virus clone 13 (LCMV clone 13). In this review, we highlight recent studies illustrating the molecular dysregulation and resultant cellular dysfunction in both innate and adaptive immune responses driven by sustained IFN-I expression. Here, we place particular emphasis on the efficacy of IFN-I receptor (IFNR) blockade towards improving immune responses against viral infections given the emerging therapeutic approach of blocking IFNR using neutralizing antibodies (Abs) in chronically infected patients.
Highlights
Type I interferons (IFN-I) are one of the primary immune defenses against viruses
Cluster of differentiation 8 (CD8) T-cell hyperactivation has been observed in hepatitis C virus (HCV)-infected patients that are continuously treated with interferon interferon (IFN-I) over seven months [7,8]
These results show that sustained IFN-I expression during persistent viral infection drives significant innate immune dysfunction, which is responsible for increased drives significant innate immune dysfunction, which is responsible for increased inflammation and immunosuppression, along with reduced antigen presentation
Summary
The type I interferon (IFN-I) system consists of five types of interferon: IFN-α, IFN-β, IFN-ω, IFN-ε, and IFN-κ. Persistent viral infections, including human immunodeficiency virus type 1 (HIV-1), are associated with prolonged dysregulation of multiple key signaling pathways, such as programmed cell death protein 1 (PD-1) and transcription factor forkhead Box O3 (FOXO3a), whose functions are critical in controlling and eliciting effective immune responses. In the face of chronic inflammation and viral persistence, these signaling pathways drive immune dysfunction that contributes to disease progression These aberrancies are reversible as illustrated by the improvement in related protective immunity upon targeted blockade of the exhaustion marker, PD-1, and transcription factor, FOXO3a. It is unsurprising that the use of humanized anti-IFNR blocking antibodies (Abs), which are currently used in a phase I trial in systemic lupus erythematosus and systemic sclerosis [39,40], are proposed to treat persistent viral infections as a means of reducing chronic inflammation [3,27,41]
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