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Cell Host Microbe. 2018 Sep 12;24(3):417-428.e5. doi: 10.1016/j.chom.2018.07.018. Epub 2018 Aug 23.

Neutralizing Antibodies Inhibit Chikungunya Virus Budding at the Plasma Membrane.

Author information

1
Blood Systems Research Institute, San Francisco, CA 94118, USA; Department of Pathology and Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: jjin@bloodsystems.org.
2
Departments of Bioengineering, Microbiology and Immunology, and Photon Science, James H. Clark Center, Stanford University, Stanford, CA 94305, USA.
3
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
4
Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA.
5
Boulder Laboratory for 3-D Electron Microscopy of Cells, Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.
6
Department of Anatomy, University of California San Francisco, San Francisco, CA 94143, USA.
7
Department of Medical Biochemistry and Biophysics, Umeå University, Umeå 901 87, Sweden.
8
Institute for Human Infections and Immunity and Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
9
Blood Systems Research Institute, San Francisco, CA 94118, USA; Department of Pathology and Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: gsimmons@bloodsystems.org.

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.

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

PMID:
30146390
PMCID:
PMC6137268
[Available on 2019-09-12]
DOI:
10.1016/j.chom.2018.07.018

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