The Dual Role of A20 (TNFAIP3) in Viral Infection: A Context-Dependent Regulator of Immunity and Pathogenesis

A20 (TNFAIP3) is a ubiquitin-editing enzyme that plays a central role in the regulation of inflammation and cell death, primarily through modulation of NF-κB signaling. In the context of viral infection, A20 exhibits a dual nature: it can both suppress antiviral immune responses to facilitate viral replication and act as a host-protective factor to prevent immunopathology. This review synthesizes current findings on the context-dependent roles of A20, focusing on its capacity to switch between antiviral and proviral functions. We examine how specific determinants—including viral genetic makeup, the infected cell type, and the temporal stage of infection—dictate whether A20 protects the host or facilitates viral persistence. We propose a systematic framework for understanding A20 as a dynamic regulator that orchestrates the balance between pathogen clearance and tissue protection.