Fc Receptors for IgG (FcγRs) on Human Monocytes and Macrophages are not Infectivity Receptors for Human Immunodeficiency Virus Type 1 (HIV-1): Studies Using Bispecific Antibodies to Target HIV-1 to Various Myeloid Cell Surface Molecules, Including the FcγR

FcγRs (FcγRI, FcγRII, and FcγRIII) are highly expressed on human mononuclear phagocytes and function in the clearance of immune complexes and opsonized pathogens. We have examined the role of FcγR in mediating antibody-dependent clearance of HIV-1 by human monocytes and monocyte-derived macrophages...

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Published in:	Proceedings of the National Academy of Sciences - PNAS 1991-11, Vol.88 (21), p.9593-9597
Main Authors:	Connor, R. I., Dinces, N. B., Howell, A. L., J.-L. Romet-Lemonne, J.-L. Pasquali, Fanger, M. W.
Format:	Article
Language:	eng
Subjects:	AIDS/HIV Antibodies Antigen-Antibody Reactions Antigens Antigens, CD - metabolism Antigens, Differentiation - physiology Antigens, Differentiation, Myelomonocytic - metabolism Biological and medical sciences CD4 Antigens - metabolism Cells, Cultured Endocytosis Fundamental and applied biological sciences. Psychology Fundamental immunology HIV 1 HIV Antibodies - metabolism HIV Core Protein p24 - metabolism HIV Infections - metabolism HIV-1 - growth & development HIV-1 - immunology HLA Antigens - metabolism human immunodeficiency virus 1 Humans Immunobiology Immunologic Techniques In Vitro Techniques Infections Macrophages Macrophages - immunology Macrophages - microbiology Molecules Monocytes Monocytes - immunology Monocytes - microbiology Monocytes, macrophages Myeloid cells: ontogeny, maturation, markers, receptors Receptors Receptors, Fc - physiology Receptors, IgG Receptors, Virus - metabolism Sialic Acid Binding Ig-like Lectin 3 Viruses
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Summary:	FcγRs (FcγRI, FcγRII, and FcγRIII) are highly expressed on human mononuclear phagocytes and function in the clearance of immune complexes and opsonized pathogens. We have examined the role of FcγR in mediating antibody-dependent clearance of HIV-1 by human monocytes and monocyte-derived macrophages by using bispecific antibodies (BsAbs) to independently target the virus to FcγRI, FcγRII, or FcγRIII. Virus production was markedly reduced in monocytes cultured with strain HIV-1IIIBopsonized with BsAbs that target the virus to either FcγRI or FcγRII compared to monocytes cultured with virus in the absence of BsAbs or in the presence of BsAbs that target the virus to non-FcγR surface antigens (CD33 and HLA-A,B,C). These results were confirmed using the monotropic isolate HIV-1JRFL. Interaction of HIV-1JRFLwith FcγRI or FcγRII on human monocytes and FcγRI, FcγRII, or FcγRIII on monocyte-derived macrophages resulted in markedly reduced levels of virus production in these cultures. Moreover, HIV-1 infection of monocytes and monocyte-derived macrophages was completely blocked by anti-CD4 monoclonal antibodies, indicating that interaction with CD4 is required for infectivity even under conditions of antibody-mediated binding of HIV-1 to FcγR. Thus, we propose that highly opsonized HIV-1 initiates high-affinity multivalent interactions with FcγR that trigger endocytosis and intracellular degradation of the antibody-virus complex. At lower levels of antibody opsonization, there are too few interactions with FcγR to initiate endocytosis and intracellular degradation of the antibody-virus complex, but there are enough interactions to stabilize the virus at the cell surface, allowing antibody-dependent enhancement of HIV-1 infection through high-affinity CD4 interactions. However, our results suggest that interaction of highly opsonized HIV-1 with FcγRs through BsAbs may reduce viral infectivity through FcγR-mediated cytotoxic mechanisms and, therefore, that BsAbs offer promise as therapeutic reagents in HIV-1 infections.
ISSN:	0027-8424 1091-6490