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Journal of Virology, October 2006, p. 10128-10138, Vol. 80, No. 20
0022-538X/06/$08.00+0     doi:10.1128/JVI.00792-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Differential Enhancement of Dengue Virus Immune Complex Infectivity Mediated by Signaling-Competent and Signaling-Incompetent Human Fc{gamma}RIA (CD64) or Fc{gamma}RIIA (CD32)

W. W. Shanaka I. Rodrigo,1 Xia Jin,2,3 Shanley D. Blackley,2 Robert C. Rose,2,3 and Jacob J. Schlesinger2,3*

Departments of Pathology and Laboratory Medicine,1 Medicine,2 Microbiology and Immunology, University of Rochester, Rochester, New York 146423

Received 18 April 2006/ Accepted 3 August 2006

Fc{gamma} receptor (Fc{gamma}R)-mediated entry of infectious dengue virus immune complexes into monocytes/macrophages is hypothesized to be a key event in the pathogenesis of complicated dengue fever. Fc{gamma}RIA (CD64) and Fc{gamma}RIIA (CD32), which predominate on the surface of such dengue virus-permissive cells, were compared for their influence on the infectivity of dengue 2 virus immune complexes formed with human dengue virus antibodies. A signaling immunoreceptor tyrosine-based activation motif (ITAM) incorporated into the accessory {gamma}-chain subunit that associates with Fc{gamma}RIA and constitutively in Fc{gamma}RIIA is required for phagocytosis mediated by these receptors. To determine whether Fc{gamma}RIA and Fc{gamma}RIIA activation functions are also required for internalization of infectious dengue virus immune complexes, we generated native and signaling-incompetent versions of each receptor by site-directed mutagenesis of ITAM tyrosine residues. Plasmids designed to express these receptors were transfected into COS-7 cells, and dengue virus replication was measured by plaque assay and flow cytometry. We found that both receptors mediated enhanced dengue virus immune complex infectivity but that Fc{gamma}RIIA appeared to do so far more effectively. Abrogation of Fc{gamma}RIA signaling competency, either by expression without {gamma}-chain or by coexpression with {gamma}-chain mutants, was associated with significant impairment of phagocytosis and of dengue virus immune complex infectivity. Abrogation of Fc{gamma}RIIA signaling competency was also associated with equally impaired phagocytosis but had no discernible effect on dengue virus immune complex infectivity. These findings point to fundamental differences between Fc{gamma}RIA and Fc{gamma}RIIA with respect to their immune-enhancing capabilities and suggest that different mechanisms of dengue virus immune complex internalization may operate between these Fc{gamma}Rs.

* Corresponding author. Mailing address: Division of Infectious Diseases, Department of Medicine, University of Rochester School of Medicine and Dentistry, Box 689, 601 Crittenden Ave., Rochester, NY 14642. Phone: (585) 275-5871. Fax: (585) 442-9328. E-mail: jacob_schlesinger{at}urmc.rochester.edu.

Journal of Virology, October 2006, p. 10128-10138, Vol. 80, No. 20
0022-538X/06/$08.00+0     doi:10.1128/JVI.00792-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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