Targeting the JAK/STAT pathway in chronic viral infections: opportunities and challenges for immunomodulation.

The discovery of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway as a key regulator of immune function and inflammation led to the development of JAK inhibitors (JAK-i), several of which are now approved for autoimmune and chronic inflammatory conditions. Recently, JAK-i have been repurposed for infectious diseases, most notably with baricitinib, a United States Food and Drug Administration (FDA)-approved JAK1/2 inhibitor for individuals hospitalized for COVID-19, demonstrating a survival benefit by dampening cytokine-mediated hyperinflammation. This has generated increased interest in leveraging JAK-i for treating people with viral infections associated with chronic immune activation, inflammation or viral persistence. This review summarizes JAK/STAT signaling in viral infections characterized by latency or chronic sequelae. We explore how modulation of this pathway may alter immune responses, impact viral control, and mitigate the consequences of chronic inflammation. We also critically examine the therapeutic potential and limitations of JAK-i in these contexts. Finally, we outline key gaps in the field and propose future directions for research into JAK/STAT targeted immunomodulation in chronic viral infections.