Human Monoclonal Antibodies against West Nile Virus Induced by Natural Infection Neutralize at a Postattachment Step

Matthew R. Vogt, Bastiaan Moesker, Jaap Goudsmit, Mandy Jongeneelen, S. Kyle Austin, Theodore Oliphant, Steevenson Nelson, Theodore C. Pierson, Jan Wilschut, Mark Throsby, Michael S. Diamond*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    81 Citations (Scopus)

    Abstract

    West Nile virus (WNV) is a neurotropic flavivirus that is now a primary cause of epidemic encephalitis in North America. Studies of mice have demonstrated that the humoral immune response against WNV limits primary infection and protects against a secondary challenge. The most-potent neutralizing mouse monoclonal antibodies (MAbs) recognize an epitope on the lateral ridge of domain III (DIII-lr) of the envelope (E) protein. However, studies with serum from human patients show that antibodies against the DIII-lr epitope comprise, at best, a minor component of the human anti-WNV antibody response. Herein, we characterize in detail two WNV-specific human MAbs, CR4348 and CR4354, that were isolated from B-cell populations of convalescent patients. These MAbs strongly neutralize WNV infection of cultured cells, protect mice against lethal infection in vivo, and yet poorly recognize recombinant forms of the E protein. Instead, CR4348 and CR4354 bind determinants on intact WNV virions and subviral particles in a pH-sensitive manner, and neutralization is altered by mutations at the dimer interface in domain II and the hinge between domains I and II, respectively. CR4348 and CR4354 human MAbs neutralize infection at a postattachment step in the viral life cycle, likely by inhibiting acid-induced fusion within the endosome.

    Original languageEnglish
    Pages (from-to)6494-6507
    Number of pages14
    JournalJournal of Virology
    Volume83
    Issue number13
    DOIs
    Publication statusPublished - Jul-2009

    Keywords

    • JAPANESE ENCEPHALITIS-VIRUS
    • TICK-BORNE ENCEPHALITIS
    • PROTEIN DOMAIN-III
    • FLAVIVIRUS ENVELOPE GLYCOPROTEIN
    • MEMBRANE-FUSION PROTEINS
    • CROSS-REACTIVE EPITOPES
    • DENGUE-VIRUS
    • MEDIATED NEUTRALIZATION
    • ANTIGENIC STRUCTURE
    • CRYSTAL-STRUCTURE

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