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

Author:

Schmitz Katharina S.1ORCID,Handrejk Kim1,Liepina Lelde2,Bauer Lisa1ORCID,Haas Griffin D.3,van Puijfelik Fabiënne1,Veldhuis Kroeze Edwin J. B.1,Riekstina Marta4,Strautmanis Jurgis2,Cao Huyen5,Verdijk Robert M.6,GeurtsvanKessel Corine H.1,van Boheemen Sander1,van Riel Debby1ORCID,Lee Benhur3ORCID,Porotto Matteo789ORCID,de Swart Rik L.1ORCID,de Vries Rory D.1ORCID

Affiliation:

1. Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands

2. Clinic for Pediatric Neurology and Neurosurgery, Children’s Clinical University Hospital, Riga, Latvia

3. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA

4. Department of Pathology, Children’s Clinical University Hospital, Riga, Latvia

5. Departments of Clinical Research, Biometrics, and Virology, Gilead Sciences, Inc., Foster City, California, USA

6. Department of Pathology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands

7. Department of Pediatrics, Columbia University Irving Medical Center, New York, New York, USA

8. Center for Host–Pathogen Interaction, Columbia University Irving Medical Center, New York, New York, USA

9. Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Caserta, Italy

Abstract

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. IMPORTANCE Measles 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.

Funder

ZonMw

HHS | National Institutes of Health

The Netherlands Organization for Scientific Research

European Society of Clinical Microbiology and Infectious Diseases

Publisher

American Society for Microbiology

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