Decoding Enterovirus 71: Molecular Functions of Structural and Nonstructural Proteins in Viral Replication and Host Manipulation

Enterovirus 71 (EV71), a member of the family Picornaviridae, genus Enterovirus, is an agent of hand, foot, and mouth disease (HFMD) and remains a persistent global health concern, particularly among children under five years of age. Although most infections are self-limiting, a significant proportion can progress to severe neurological manifestations such as aseptic meningitis, encephalitis, and fatal pulmonary oedema. Despite substantial advances in research, no universally effective antiviral therapy or broadly protective vaccine has yet been developed. Drawing upon both foundational and recent studies, we evaluate the strength of existing evidence and delineate how these viral proteins cooperatively regulate viral entry, genome replication, immune evasion, autophagy, and host cell death. Special emphasis is placed on virus–host protein interactions, post-translational modifications, and the signaling pathways targeted by EV71 to subvert innate immune responses protein–protein interactions with host factors, post-translational modifications, and the molecular mechanisms by which EV71 subverts innate immune signaling pathways. By integrating structural, biochemical, and systems-level insights, this review pro-poses a unifying conceptual model of EV71 protein function, highlighting key molecular interfaces that underline viral replication and pathogenesis. The analysis also identifies critical knowledge gaps and emerging therapeutic targets, providing a forward-looking perspective on strategies for antiviral drug discovery, vaccine design, and host-directed interventions aimed at durable control of EV71 infection. This review was designed to critically synthesize current structural, molecular, and systems-level evidence to elucidate how EV71 structural and nonstructural proteins coordinate viral replication, immune evasion, and pathogenesis, and to identify priority targets for antiviral and vaccine development.