Fc receptors for IgG (Fc gamma Rs) 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 Fc gamma R.
Fc gamma Rs (Fc gamma RI, Fc gamma RII, and Fc gamma RIII) are highly expressed on human mononuclear phagocytes and function in the clearance of immune complexes and opsonized pathogens. We have examined the role of Fc gamma R 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 Fc gamma RI, Fc gamma RII, or Fc gamma RIII. Virus production was markedly reduced in monocytes cultured with strain HIV-1IIIB opsonized with BsAbs that target the virus to either Fc gamma RI or Fc gamma RII compared to monocytes cultured with virus in the absence of BsAbs or in the presence of BsAbs that target the virus to non-Fc gamma R surface antigens (CD33 and HLA-A,B,C). These results were confirmed using the monotropic isolate HIV-1JRFL. Interaction of HIV-1JRFL with Fc gamma RI or Fc gamma RII on human monocytes and Fc gamma RI, Fc gamma RII, or Fc gamma RIII 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 Fc gamma R. Thus, we propose that highly opsonized HIV-1 initiates high-affinity multivalent interactions with Fc gamma R that trigger endocytosis and intracellular degradation of the antibody-virus complex. At lower levels of antibody opsonization, there are two few interactions with Fc gamma R 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 Fc gamma Rs through BsAbs may reduce viral infectivity through Fc gamma R-mediated cytotoxic mechanisms and, therefore, that BsAbs offer promise as therapeutic reagents in HIV-1 infections.
Connor
R I
RI
Department of Microbiology, Dartmouth Medical School, Hanover, NH 03756.
Dinces
N B
NB
Howell
A L
AL
Romet-Lemonne
J L
JL
Pasquali
J L
JL
Fanger
M W
MW
D000937:Antigen-Antibody Reactions; D015703:Antigens, CD / Q000378:metabolism; D000943:Antigens, Differentiation / Q000502:physiology*; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D015483:HIV Antibodies / Q000378:metabolism; D016655:HIV Core Protein p24 / Q000378:metabolism; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1 / Q000254:growth & development* / Q000276:immunology; D006680:HLA Antigens / Q000378:metabolism; D006801:Humans; D007158:Immunologic Techniques; D066298:In Vitro Techniques; D008264:Macrophages / Q000276:immunology / Q000382:microbiology*; D009000:Monocytes / Q000276:immunology / Q000382:microbiology*; D011961:Receptors, Fc / Q000502:physiology*; D017452:Receptors, IgG; D011991:Receptors, Virus / Q000378:metabolism*; D063268:Sialic Acid Binding Ig-like Lectin 3
D015703:Antigens, CD; D000943:Antigens, Differentiation; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; D015704:CD4 Antigens; D015483:HIV Antibodies; D016655:HIV Core Protein p24; D006680:HLA Antigens; D011961:Receptors, Fc; D017452:Receptors, IgG; D011991:Receptors, Virus; D063268:Sialic Acid Binding Ig-like Lectin 3