Interferon-stimulated restriction factors in enterovirus infection: A review on the mechanisms and antiviral roles of shiftless (C19orf66).

Enteroviruses are positive-sense single-stranded RNA viruses that cause a wide spectrum of human diseases, ranging from mild febrile illness to severe neurological complications. Although most infections are self-limiting, certain strains cause significant morbidity, particularly in young children. The infection outcome largely depends on the balance between viral replication efficiency and host antiviral responses. Among host antiviral responses, type I interferon signaling plays a central role in restricting enterovirus replication by inducing interferon-stimulated genes. This review summarizes the current understanding of interferon-mediated restriction mechanisms targeting enteroviruses, with a particular focus on representative antiviral effectors, including IFITs, PKR, OAS/RNase L, ZAP, and shiftless (SHFL, also known as C19orf66). SHFL has become an important interferon-stimulated restriction factor with antiviral activity against several RNA viruses, including enteroviruses. In enteroviruses, current evidence supports the role of SHFL in targeting viral replication proteins (such as 3Dpol) and reducing viral RNA accumulation, while other mechanisms described in other RNA viruses, including their effects on viral translation, have been discussed as potential or context-dependent activities. In addition, enteroviruses have evolved mechanisms to counteract interferon signaling and restriction factor activity, highlighting the sustained interaction between virus replication and host intrinsic immunity. A comprehensive understanding of interferon-stimulated restriction factors and virus evasion strategies may provide new insights into the pathogenesis of enteroviruses and guide future host-directed antiviral research.