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

Autor:	Schmitz KS; Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands., Handrejk K; Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands., Liepina L; Clinic for Pediatric Neurology and Neurosurgery, Children's Clinical University Hospital, Riga, Latvia., Bauer L; Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands., Haas GD; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA., van Puijfelik F; Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands., Veldhuis Kroeze EJB; Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands., Riekstina M; Department of Pathology, Children's Clinical University Hospital, Riga, Latvia., Strautmanis J; Clinic for Pediatric Neurology and Neurosurgery, Children's Clinical University Hospital, Riga, Latvia., Cao H; Departments of Clinical Research, Biometrics, and Virology, Gilead Sciences, Inc., Foster City, California, USA., Verdijk RM; Department of Pathology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands., GeurtsvanKessel CH; Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands., van Boheemen S; Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands., van Riel D; Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands., Lee B; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Porotto M; Department of Pediatrics, Columbia University Irving Medical Center, New York, New York, USA.; Center for Host-Pathogen Interaction, Columbia University Irving Medical Center, New York, New York, USA.; Department of Experimental Medicine, University of Campania 'Luigi Vanvitelli', Caserta, Italy., de Swart RL; Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands., de Vries RD; Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.
Jazyk:	angličtina
Zdroj:	Journal of virology [J Virol] 2024 Mar 19; Vol. 98 (3), pp. e0187423. Date of Electronic Publication: 2024 Feb 08.
DOI:	10.1128/jvi.01874-23
Abstrakt:	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.IMPORTANCEMeasles virus (MeV) causes acute, systemic disease and remains an important cause of morbidity and mortality in humans. Despite the lack of known entry receptors in the brain, MeV can persistently infect the brain causing the rare but fatal neurological disorder subacute sclerosing panencephalitis (SSPE). SSPE-causing MeVs are characterized by a hypermutated genome and a hyperfusogenic F protein that facilitates the rapid spread of MeV throughout the brain. No treatment against SSPE is available, but the nucleoside analog remdesivir was recently demonstrated to be effective against MeV in vitro . We show that treatment of an SSPE patient with remdesivir led to transient clinical improvement and did not induce viral escape mutants, encouraging the future use of remdesivir in SSPE patients. Functional characterization of the viral proteins sheds light on the shared properties of SSPE-causing MeVs and further contributes to understanding how those viruses cause disease. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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