Prevention of measles virus infection by intranasal delivery of fusion inhibitor peptides.
Measles virus (MV) infection is undergoing resurgence and remains one of the leading causes of death among young children worldwide despite the availability of an effective measles vaccine. MV infects its target cells by coordinated action of the MV H and the fusion (F) envelope glycoprotein; upon receptor engagement by H, the prefusion F undergoes a structural transition, extending and inserting into the target cell membrane and then refolding into a postfusion structure that fuses the viral and cell membranes. By interfering with this structural transition of F, peptides derived from the heptad-repeat (HR) regions of F can potently inhibit MV infection at the entry stage. We show here that specific features of H's interaction with its receptors modulate the susceptibility of MV F to peptide fusion inhibitors. A higher concentration of inhibitory peptides is required to inhibit F-mediated fusion when H is engaged to its nectin-4 receptor than when H is engaged to its CD150 receptor. Peptide inhibition of F may be subverted by continued engagement of receptor by H, a finding that highlights the ongoing role of H-receptor interaction after F has been activated and that helps guide the design of more potent inhibitory peptides. Intranasal administration of these peptides results in peptide accumulation in the airway epithelium with minimal systemic levels of peptide and efficiently prevents MV infection in vivo in animal models. The results suggest an antiviral strategy for prophylaxis in vulnerable and/or immunocompromised hosts.


OBJECTIVE
Measles virus (MV) infection causes an acute illness that may be associated with infection of the central nervous system (CNS) and severe neurological disease. No specific treatment is available. We have shown that parenterally delivered fusion-inhibitory peptides protect mice from lethal CNS MV disease. Here we show, using established small-animal models of MV infection, that fusion-inhibitory peptides delivered intranasally provide effective prophylaxis against MV infection. Since the fusion inhibitors are stable at room temperature, this intranasal strategy is feasible even outside health care settings, could be used to protect individuals and communities in case of MV outbreaks, and could complement global efforts to control measles.
Department of Microbiology and Immunology and Department of Pediatrics, Weill Medical College of Cornell University, New York, New York, USA CIRI, International Center for Infectiology Research, Lyon, France Inserm, U1111, Lyon, France CNRS, UMR5308, Lyon, France Université Lyon 1, Lyon, France Ecole Normale Supérieure de Lyon, Lyon, France.
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Mathieu
Inserm, U1111, Lyon, France.
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Huey
Department of Microbiology and Immunology and Department of Pediatrics, Weill Medical College of Cornell University, New York, New York, USA.
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Jurgens
CIRI, International Center for Infectiology Research, Lyon, France Inserm, U1111, Lyon, France CNRS, UMR5308, Lyon, France Université Lyon 1, Lyon, France Ecole Normale Supérieure de Lyon, Lyon, France.
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Welsch
Department of Microbiology and Immunology and Department of Pediatrics, Weill Medical College of Cornell University, New York, New York, USA.
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DeVito
Department of Microbiology and Immunology and Department of Pediatrics, Weill Medical College of Cornell University, New York, New York, USA.
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Talekar
CIRI, International Center for Infectiology Research, Lyon, France Inserm, U1111, Lyon, France CNRS, UMR5308, Lyon, France Université Lyon 1, Lyon, France Ecole Normale Supérieure de Lyon, Lyon, France.
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B
Horvat
Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA.
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Niewiesk
Department of Microbiology and Immunology and Department of Pediatrics, Weill Medical College of Cornell University, New York, New York, USA anm2047@med.cornell.edu map2028@med.cornell.edu.
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Moscona
Department of Microbiology and Immunology and Department of Pediatrics, Weill Medical College of Cornell University, New York, New York, USA anm2047@med.cornell.edu map2028@med.cornell.edu.
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Porotto
D000281:Administration, Intranasal; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D018890:Chemoprevention / Q000379:methods; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D008457:Measles / Q000517:prevention & control*; D008459:Measles virus / Q000187:drug effects*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000008:administration & dosage*; D016205:Sigmodontinae; D014760:Viral Fusion Proteins / Q000008:administration & dosage*; D053586:Virus Internalization / Q000187:drug effects*
D000998:Antiviral Agents; D009842:Oligopeptides; D014760:Viral Fusion Proteins