Immune Evasion by Neurotropic Viruses: Molecular Strategies, Cellular Targets, and Consequences for CNS Infection

Neurotropic viruses have evolved sophisticated mechanisms to evade host immune responses within the central nervous system (CNS), enabling viral replication, persistence, latency, and neuropathogenesis while minimizing irreversible neuronal damage. Unlike peripheral tissues, the CNS requires tightly regulated antiviral immunity to balance effective pathogen control with the preservation of neural function. This review examines the diverse yet convergent immune evasion strategies employed by major neurotropic RNA and DNA viruses, including herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), rabies virus (RABV), flaviviruses, alphaviruses, enteroviruses, and JC virus (JCV). We discuss viral interference with innate immune sensing pathways, including RIG-I-like receptors (RLRs) and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling, inhibition of type I interferon induction and Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling, modulation of interferon-stimulated effector mechanisms, and disruption of antigen presentation and adaptive immune surveillance. The review further highlights the distinct roles of viral latency, long-term persistence, neuronal-glial interactions, and metabolic reprogramming in facilitating prolonged infection within the CNS. Emerging evidence indicates that successful neurotropic viruses rarely achieve immune evasion through complete suppression of host defenses; instead, they fine-tune antiviral responses to preserve host cell viability while preventing viral clearance. Finally, we discuss current knowledge gaps and emphasize the need for advanced human-relevant models, single-cell and spatial multi-omics, and systems-level approaches to better define virus-host interactions within the CNS. A deeper understanding of these integrated immune evasion networks may reveal novel therapeutic strategies that enhance antiviral immunity while limiting neuroinflammation and preserving neurological function.