Does fever drive the evolution of antiviral genes?

Fever is an evolutionarily conserved response to infection that emerged ∼600 million years ago, providing survival benefits across diverse taxa from insects to mammals. While fever's protective mechanisms include moving pathogens outside their thermal optima and enhancing cellular immune responses, this Perspective proposes the hypothesis that antiviral genes may have evolved to function optimally at fever temperatures rather than baseline body temperature. IFN-stimulated genes (ISGs) could exhibit temperature-dependent functionality, with enhanced antiviral activity during febrile episodes when viral loads peak. Current mechanistic studies conducted at physiological temperatures (e.g., 37°C for humans) may miss critical antiviral interactions occurring at fever temperatures (38-42°C). Comparative analysis across species with varying basal body temperatures, combined with advances in protein thermal stability prediction, could reveal temperature-dependent signatures of selection in antiviral genes. Understanding fever's role in shaping antiviral gene evolution may illuminate blind spots in our comprehension of host-pathogen interactions and antiviral mechanisms.