Measles-like hypermutation of a Newcastle disease virus drives fatal encephalitis during BCMA × CD3 T-cell-redirecting immunotherapy

Abstract Newcastle disease virus (NDV or AOaV-1) is an avian paramyxovirus that typically causes only mild, self-limiting disease in humans. Here, we report fatal neuroinvasive AOaV-1 infection in a patient with multiple myeloma receiving maintenance therapy with teclistamab, daratumumab, and lenalidomide following frontline teclistamab-based treatment and autologous stem cell transplantation. Following rapidly progressive brainstem–cerebellar encephalitis and negative conventional microbiological testing, unbiased metagenomic RNA sequencing of a cerebellar biopsy identified AOaV-1 at high intraparenchymal abundance. Viral genome analysis revealed striking A-to-G and U-to-C substitutions selectively concentrated in the matrix gene, consistent with ADAR-mediated RNA editing. Long-read sequencing resolved two genetically distinct, independently hypermutated CNS haplotypes. Post-mortem analysis demonstrated widespread dissemination and continued viral diversification in multiple brain regions, whereas a peripheral urine sample contained a minimally mutated putative ancestral lineage. These findings support peripheral infection followed by CNS seeding and compartmentalized within-host evolution. The selective matrix-gene hypermutation closely parallels persistent measles virus infection in subacute sclerosing panencephalitis, revealing a shared mechanism of paramyxovirus adaptation to the CNS. Profound immunotherapy-associated immune dysfunction may thus create niches enabling normally low-pathogenic zoonotic viruses to persist, evolve, and acquire severe neurovirulence.