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How a paramyxovirus fusion/entry complex adapts to escape a neutralizing antibody
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Journal Article
How a paramyxovirus fusion/entry complex adapts to escape a neutralizing antibody
2024
Overview
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.
Monoclonal antibodies hold promise for combating serious respiratory virus infections but viruses may evolve to evade them. Here, using structural analysis, the authors show how human parainfluenza virus adapts to escape a powerful antibody by modulating its cell entry mechanism.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ Animals
/ Antibodies, Monoclonal - immunology
/ Antibodies, Neutralizing - immunology
/ Antibodies, Viral - immunology
/ Humanities and Social Sciences
/ Humans
/ Mutation
/ Parainfluenza Virus 3, Human - immunology
/ Proteins
/ Science
/ Viral Fusion Proteins - chemistry
/ Viral Fusion Proteins - immunology
/ Viral Fusion Proteins - metabolism
/ Virions
/ Viruses
