Functional properties of measles virus proteins derived from a subacute sclerosing panencephalitis patient who received repeated remdesivir treatments

Katharina S. Schmitz, Kim Handrejk, Lelde Liepina, Lisa Bauer, Griffin D. Haas, Fabiënne van Puijfelik, Edwin J.B. Veldhuis Kroeze, Marta Riekstina, Jurgis Strautmanis, Huyen Cao, Robert M. Verdijk, Corine H. GeurtsvanKessel, Sander van Boheemen, Debby van Riel, Benhur Lee, Matteo Porotto, Rik L. de Swart, Rory D. de Vries

Research output: Contribution to journalArticlepeer-review

Abstract

Subacute sclerosing panencephalitis (SSPE) is a rare but fatal late neurological complication of measles, caused by persistent measles virus (MeV) infection of the central nervous system. There are no drugs approved for the treatment of SSPE. Here, we followed the clinical progression of a 5-year-old SSPE patient after treatment with the nucleoside analog remdesivir, conducted a post-mortem evaluation of the patient’s brain, and characterized the MeV detected in the brain. The quality of life of the patient transiently improved after the first two courses of remdesivir, but a third course had no further clinical effect, and the patient eventually succumbed to his condition. Post-mortem evaluation of the brain displayed histopathological changes including loss of neurons and demyelination paired with abundant presence of MeV RNA-positive cells throughout the brain. Next-generation sequencing of RNA isolated from the brain revealed a complete MeV genome with mutations that are typically detected in SSPE, characterized by a hypermutated M gene. Additional mutations were detected in the polymerase (L) gene, which were not associated with resistance to remdesivir. Functional characterization showed that mutations in the F gene led to a hyperfusogenic phenotype predominantly mediated by N465I. Additionally, recombinant wild-type-based MeV with the SSPE-F gene or the F gene with the N465I mutation was no longer lymphotropic but instead efficiently disseminated in neural cultures. Altogether, this case encourages further investigation of remdesivir as a potential treatment of SSPE and highlights the necessity to functionally understand SSPE-causing MeV.

Original languageEnglish
JournalJournal of Virology
Volume98
Issue number3
DOIs
StatePublished - Mar 2024

Keywords

  • fusion
  • measles
  • remdesivir
  • resistance
  • subacute sclerosing panencephalitis

Fingerprint

Dive into the research topics of 'Functional properties of measles virus proteins derived from a subacute sclerosing panencephalitis patient who received repeated remdesivir treatments'. Together they form a unique fingerprint.

Cite this