Differentiation and Protective Capacity of Virus-Specific CD8⁺ T Cells Suggest Murine Norovirus Persistence in an Immune-Privileged Enteric Niche

Noroviruses can establish chronic infections with active viral shedding in healthy humans but whether persistence is associated with adaptive immune dysfunction is unknown. We used genetically engineered strains of mouse norovirus (MNV) to investigate CD8⁺ T cell differentiation during chronic infection. We found that chronic infection drove MNV-specific tissue-resident memory (Trm) CD8⁺ T cells to a differentiation state resembling inflationary effector responses against latent cytomegalovirus with only limited evidence of exhaustion. These MNV-specific Trm cells remained highly functional yet appeared ignorant of ongoing viral replication. Pre-existing MNV-specific Trm cells provided partial protection against chronic infection but largely ceased to detect virus within 72 hours of challenge, demonstrating rapid sequestration of viral replication away from T cells. Our studies revealed a strategy of immune evasion by MNV via the induction of a CD8⁺ T cell program normally reserved for latent pathogens and persistence in an immune-privileged enteric niche. Chronic infections often cause T cell dysfunction, but how noroviruses (NV) evade immunity is unknown. Tomov et al. show that gut-resident T cells against NV remain functional but ignorant of chronic viral replication, suggesting that NV persists in an immune-privileged enteric niche.