Recombinant CD4-IgE, a novel hybrid molecule, inducing basophils to respond to human immunodeficiency virus (HIV) and HIV-infected target cells.
Basophils and mast cells, as the main effector cells in IgE-mediated type I hypersensitivity, are involved in the elimination of parasites and, according to recent findings, may also play an important role in the defense against bacterial and viral infections. Using a genetic engineering approach we wanted to redirect this potent IgE-mediated defense system against intruding human immune deficiency virus. We constructed a recombinant CD4-IgE molecule, consisting of the two N-terminal domains of CD4 and the CH2-4 domains of the IgE heavy chain, thus providing the IgE with specificity for the gp120 of human immunodeficiency virus (HIV). The binding properties of hybrid CD4-IgE to the high-affinity receptor for IgE (Fc epsilon RI) on basophils as well as to the low-affinity receptor (Fc epsilon RII or CD23) for IgE on lymphoid cells were found to be similar to those of native IgE. At the same time, the CD4 domains of the recombinant molecule retained the gp120 binding specificity with an affinity similar to that of the native CD4. By functional tests, we demonstrated that CD4-IgE armed basophils can be triggered by free HIV and by HIV-infected cells to release their mediators. We further show that HIV-triggered basophils lead to a decreased replication of HIV in susceptible T cells. We, therefore, conclude that the type I hypersensitivity effector cells can be engaged in the elimination of HIV-infected cells, at least in vitro. Because of the strong binding of the CD4-IgE construct to the Fc epsilon RI, we assume that CD4-IgE has a short t1/2 in serum, but may similarly to IgE exhibit prolonged resident time on basophils and mast cells, which are located close to mucosal surfaces or in the connective tissue. Thus CD4-IgE could play an important role in the elimination of HIV also in vivo.
Krauss
S
S
Institute for Immunology, University of Munich, Germany.
Kufer
P
P
Federle
C
C
Tabaszewski
P
P
Weiss
E
E
Rieber
E P
EP
Riethmüller
G
G
D001491:Basophils / Q000276:immunology*; D015153:Blotting, Western; D015704:CD4 Antigens / Q000096:biosynthesis / Q000276:immunology*; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D006678:HIV / Q000276:immunology*; D015488:HIV Antigens / Q000276:immunology; D006636:Histamine Release / Q000276:immunology; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000276:immunology*; D017455:Receptors, IgE / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000276:immunology
D015704:CD4 Antigens; D015488:HIV Antigens; D017455:Receptors, IgE; D011993:Recombinant Fusion Proteins; D007073:Immunoglobulin E