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Updated: Jun 10, 2025
Generation of Escape Variants of Neutralizing Influenza Virus Monoclonal Antibodies
Published on: August 29, 2017
How a paramyxovirus fusion/entry complex adapts to escape a neutralizing antibody
Tara C Marcink1,2, Gillian Zipursky3,4, Elizabeth B Sobolik5
1Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA. tm2996@cumc.columbia.edu.
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.
Insights
Paramyxoviruses like HPIV3 pose health risks. New structures reveal how viral mutations allow resistance to antibody therapies by altering the fusion complex, guiding future drug design.
Area of Science:
- Virology
- Structural Biology
- Immunology
Background:
- Paramyxoviruses, including measles, Nipah, and parainfluenza viruses, represent significant public health concerns with pandemic potential.
- Human parainfluenza virus type 3 (HPIV3) is a major cause of illness in vulnerable populations, and currently lacks approved vaccines or therapeutics.
- Neutralizing monoclonal antibodies (mAbs) targeting viral fusion proteins offer a potential therapeutic strategy, but viral evolution can lead to resistance.
Purpose of the Study:
- To investigate the structural basis of HPIV3 resistance to neutralizing monoclonal antibodies (mAbs).
- To elucidate the mechanisms by which paramyxoviruses adapt to evade antibody-mediated neutralization.
- To provide insights for designing broadly effective antibody-based therapies against paramyxoviruses.
Main Methods:
- Cryo-electron tomography (cryo-ET) was used to determine the structures of pre-fusion HN-F complexes.
- Structures were obtained in situ on virions that had evolved resistance to an anti-HPIV3 F neutralizing mAb.
- Analysis focused on the conformational changes in the HN-F complex associated with mAb resistance.
Main Results:
- Cryo-ET revealed structures of pre-fusion HN-F complexes on resistant HPIV3 virions.
- Single mutations in the fusion (F) protein were sufficient to abolish mAb binding and confer neutralization resistance.
- In resistant complexes, the HN protein shifted, uncapping the F protein apex and facilitating fusion.
- These structural rearrangements indicate increased readiness for viral fusion.
Conclusions:
- Paramyxoviruses exhibit adaptability in their pre-fusion HN-F complex structure, enabling resistance to neutralizing mAbs.
- Viral evolution can overcome antibody therapies through specific mutations altering the HN-F complex dynamics.
- Understanding these resistance mechanisms is crucial for designing next-generation antibody therapeutics with durable efficacy.
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