JVI Accepts, published online ahead of print on 20 May 2009

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J. Virol. doi:10.1128/JVI.00656-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Utilization of IgG Fc Receptors by Human Immunodeficiency Virus Type 1: A Specific Role for Antibodies Against the Membrane Proximal External Region of gp41

Lautaro G. Perez, Matthew R. Costa, Christopher A. Todd, Barton F. Haynes, and David C. Montefiori^*

Departments of Surgery and Medicine, Duke University Medical Center, Durham, North Carolina 27710

^* To whom correspondence should be addressed. Email: monte{at}duke.edu.

Receptors for the constant region of immunoglobulin G (FcR) are an important link between humoral and cellular immunity. To help define the role of FcRs in determining the fate of HIV-1 immune complexes, cDNAs for the four major human Fc receptors (FcRI, FcRIIa, FcRIIb, FcRIIIa) were stably expressed by lentiviral transduction in a cell line (TZM-bl) commonly used for standardized assessments of HIV-1 neutralization. Individual cell lines, each expressing a different FcR, bound human IgG as evidence that the physical properties of the receptors were preserved. In assays with a multi-subtype panel of HIV-1 viruses, the neutralizing activity of two monoclonal antibodies (2F5 and 4E10) that target the membrane proximal external region (MPER) of gp41 was potentiated FcRI and, to a lesser extent, by FcRIIb. Moreover, the neutralizing activity of an HIV-1-positive plasma sample known to contain gp41 MPER-specific antibodies was potentiated by FcRI. The neutralizing activity of monoclonal antibodies b12 and 2G12 and other HIV-1-positive plasma samples was rarely affected by any of the four FcRs. Effects with gp41 MPER-specific antibodies were moderately stronger for IgG1 compared to IgG3 and were ineffective for Fab. We conclude that FcRI and FcRIIb facilitate antibody-mediated neutralization of HIV-1 by a mechanism that is dependent on the Fc region, IgG subclass and epitope specificity of antibody. The FcR effects seen here suggests that the MPER of gp41 could have greater value for vaccines than previously recognized.

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