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.