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| Title | How a paramyxovirus fusion/entry complex adapts to escape a neutralizing antibody. |
|---|---|
| Journal, issue, pages | Nat Commun, Vol. 15, Issue 1, Page 8831, Year 2024 |
| Publish date | Oct 12, 2024 |
 Authors | Tara C Marcink / Gillian Zipursky / Elizabeth B Sobolik / Kate Golub / Emily Herman / Kyle Stearns / Alexander L Greninger / Matteo Porotto / Anne Moscona /   |
| PubMed 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 ...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. |
 External links | Nat Commun / PubMed:39396053 / PubMed Central |
| Methods | EM (subtomogram averaging) |
| Resolution | 12.2 - 13.2 Å |
| Structure data |  EMDB-43912: Subtomogram average of the HN-F complex on the viral surface of an HPIV3 escape variant mutation (F-L234F).  EMDB-43913: Subtomogram average of the HN-F complex on the viral surface of an HPIV3 escape variant (EV2).  EMDB-43914: Subtomogram average of the HN-F complex on the viral surface of an HPIV3 escape variant (EV1). |
