How a paramyxovirus fusion/entry complex adapts to escape a neutralizing antibody

Tara C. Marcink (), Gillian Zipursky, Elizabeth B. Sobolik, Kate Golub, Emily Herman, Kyle Stearns, Alexander L. Greninger, Matteo Porotto and Anne Moscona ()
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Tara C. Marcink: Columbia University Vagelos College of Physicians and Surgeons
Gillian Zipursky: Columbia University Vagelos College of Physicians and Surgeons
Elizabeth B. Sobolik: University of Washington
Kate Golub: Columbia University Vagelos College of Physicians and Surgeons
Emily Herman: Columbia University Vagelos College of Physicians and Surgeons
Kyle Stearns: Columbia University Vagelos College of Physicians and Surgeons
Alexander L. Greninger: University of Washington
Matteo Porotto: Columbia University Vagelos College of Physicians and Surgeons
Anne Moscona: Columbia University Vagelos College of Physicians and Surgeons

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Paramyxoviruses including measles, Nipah, and parainfluenza viruses are public health threats with pandemic potential. Human parainfluenza virus type 3 (HPIV3) is a leading cause of illness in pediatric, older, and immunocompromised populations. There are no approved vaccines or therapeutics for HPIV3. Neutralizing monoclonal antibodies (mAbs) that target viral fusion are a potential strategy for mitigating paramyxovirus infection, however their utility may be curtailed by viral evolution that leads to resistance. Paramyxoviruses enter cells by fusing with the cell membrane in a process mediated by a complex consisting of a receptor binding protein (HN) and a fusion protein (F). Existing atomic resolution structures fail to reveal physiologically relevant interactions during viral entry. We present cryo-ET structures of pre-fusion HN-F complexes in situ on surfaces of virions that evolved resistance to an anti-HPIV3 F neutralizing mAb. Single mutations in F abolish mAb binding and neutralization. In these complexes, the HN protein that normally restrains F triggering has shifted to uncap the F apex. These complexes are more readily triggered to fuse. These structures shed light on the adaptability of the pre-fusion HN-F complex and mechanisms of paramyxoviral resistance to mAbs, and help define potential barriers to resistance for the design of mAbs.

Date: 2024
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DOI: 10.1038/s41467-024-53082-y

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