Neutralizing Antibodies Inhibit Chikungunya Virus Budding at the Plasma Membrane

Jing Jin, Jesús G. Galaz-Montoya, Michael B. Sherman, Stella Y. Sun, Cynthia S. Goldsmith, Eileen T. O'Toole, Larry Ackerman, Lars Anders Carlson, Scott C. Weaver, Wah Chiu, Graham Simmons

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Neutralizing antibodies (NAbs) are traditionally thought to inhibit virus infection by preventing virion entry into target cells. In addition, antibodies can engage Fc receptors (FcRs) on immune cells to activate antiviral responses. We describe a mechanism by which NAbs inhibit chikungunya virus (CHIKV), the most common alphavirus infecting humans, by preventing virus budding from infected human cells and activating IgG-specific Fcγ receptors. NAbs bind to CHIKV glycoproteins on the infected cell surface and induce glycoprotein coalescence, preventing budding of nascent virions and leaving structurally heterogeneous nucleocapsids arrested in the cytosol. Furthermore, NAbs induce clustering of CHIKV replication spherules at sites of budding blockage. Functionally, these densely packed glycoprotein-NAb complexes on infected cells activate Fcγ receptors, inducing a strong, antibody-dependent, cell-mediated cytotoxicity response from immune effector cells. Our findings describe a triply functional antiviral pathway for NAbs that might be broadly applicable across virus-host systems, suggesting avenues for therapeutic innovation through antibody design. Jin et al. demonstrate that neutralizing antibodies (NAbs) inhibit chikungunya virus budding by inducing viral glycoprotein coalescence on infected cells. NAbs that crosslink glycoproteins engage Fc receptors on immune cells to activate antiviral responses. Considering the classical entry-inhibition function of NAbs, this work describes a triply functional antiviral pathway for NAbs.

Original languageEnglish (US)
Pages (from-to)417-428.e5
JournalCell Host and Microbe
Volume24
Issue number3
DOIs
StatePublished - Sep 12 2018

Keywords

  • chikungunya virus (CHIKV)
  • cryoelectron tomography (cryoET)
  • glycoproteins (GPs)
  • immunoelectron microscopy (IEM)
  • neutralizing antibodies (NAbs)
  • nucleocapsid-like particles (NCLPs)
  • stimulated emission depletion microscopy (STED)
  • subtomogram averaging (STA)
  • transmission electron microscopy (TEM)
  • virus budding

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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