Functional and antigenic constraints on the Nipah virus fusion

• 成果类型: Article
• 署名作者: Larsen, Brendan B.; Harari, Sheri; Gen, Risako; Stewart, Cameron; Veesler, David; Bloom, Jesse D.
• 署名单位: Fred Hutchinson Cancer Center; Fred Hutchinson Cancer Center; University of Washington; University of Washington Seattle; Howard Hughes Medical Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2529505123
• 发表日期: 2026-02-10
• 页码: e2529505123
• 关键词: class I fusion protein; deep mutational scanning; pseudovirus; paramyxovirus; hendra-virus; membrane-fusion; paramyxovirus fusion; CYTOPLASMIC TAIL; structural basis; protein; glycoprotein; activation; attachment; receptor

摘要

Nipah virus is a highly pathogenic virus in the family Paramyxoviridae that utilizes two distinct surface glycoproteins to infect cells. The receptor-binding protein (RBP) binds host receptors whereas the fusion protein (F) merges viral and host membranes. Here, we use nonreplicative pseudoviruses to safely measure the effects of all F single amino acid residue mutations on its cell entry function and neutralization by monoclonal antibodies. We compare mutational tolerance in F with previous experimental measurements for RBP and show that F is much more functionally constrained than the RBP. We also identify mutationally intolerant sites on the F trimer surface and core that are critical for proper function, and describe mutations that are candidates for stabilizing F in the prefusion conformation for vaccine design. We quantify how F mutations affect neutralization by six monoclonal antibodies, and show that the magnitude of mutational effects on neutralization varies among antibodies. Our measurements of mutational effects on Nipah virus F predict the ability of the antibodies to neutralize the related Hendra virus. Overall, our work defines the functional and antigenic constraints on the F protein from an important zoonotic virus.