Inhibition of Human Immunodeficiency Virus Type 1 gp120 Presentation to CD4 T Cells by Antibodies Specific for the CD4 Binding Domain of gp120

Abstract

Human immunodeficiency virus (HIV)-specific CD4T-cell responses, particularly to the envelope glycoproteins of the virus, are weak or absent in most HIV-infected patients. Although these poor responses can be attributed simply to the destruction of the specific CD4 T cells by the virus, other factors also appear to contribute to the suppression of these virus-specific responses. We previously showed that human monoclonal antibodies (MAbs) specific for the CD4 binding domain of gp120 (gp120 CD4BD ), when complexed with gp120, inhibited the proliferative responses of gp120-specific CD4 T-cells. MAbs to other gp120 epitopes did not exhibit this activity. The present study investigated the inhibitory mechanisms of the anti-gp120 CD4BD MAbs. The anti-gp120 CD4BD MAbs complexed with gp120 suppressed gamma interferon production as well as proliferation of gp120-specific CD4 T cells. Notably, the T-cell responses to gp120 were inhibited only when the MAbs were added to antigen-presenting cells (APCs) during antigen pulse; the addition of the MAbs after pulsing caused no inhibition. However, the anti-gp120 CD4BD MAbs by themselves, or as MAb/gp120 complexes, did not affect the presentation of gp120-derived peptides by the APCs to T cells. These MAb/gp120 complexes also did not inhibit the ability of APCs to process and present unrelated antigens. To test whether the suppressive effect of anti-gp120 CD4BD antibodies is caused by the antibodies' ability to block gp120-CD4 interaction, APCs were treated during antigen pulse with anti-CD4 MAbs. These treated APCs remained capable of presenting gp120 to the T cells. These results suggest that anti-gp120 CD4BD Abs inhibit gp120 presentation by altering the uptake and/or processing of gp120 by the APCs but their inhibitory activity is not due to blocking of gp120 attachment to CD4 on the surface of APCs.

Opsonization of HIV with Complement Enhances Infection of Dendritic Cells and Viral Transfer to CD4 T Cells in a CR3 and DC-SIGN-Dependent Manner

“…In contrast, blocking mAb directed to CD4 receptor did not exhibit a differential effect on inhibition of infection with AC-OV and HIC-OV X4-tropic HIV-1 NDK and R5-tropic HIV-1 BAL . This result agrees with the observation that the CD4 binding site on gp120 does not implicate complement-activating sites such as C2, V2, C5, and V3 loop (35). Opsonization of HIV by complement probably enhances the binding to CR3 receptor and increases the number of viral particles adsorbed on cells allowing a more efficient fusion and viral entry through CD4 and HIV coreceptors.…”

Human Immunodeficiency Virus Type 1 Evades T-Helper Responses by Exploiting Antibodies That Suppress Antigen Processing

“…T-cell-proliferative responses to recombinant gp120 and AT-2-inactivated virions were assessed by [ 3 H]thymidine uptake as previously described (3,17,18). Briefly, recombinant gp120 or diluted AT-2-inactivated virions were incubated alone or with Abs at the designated concentrations for 3 h at 37°C.…”

“…Earlier studies identified a novel factor contributing to the abrogation of glycoprotein 120 (gp120)-specific CD4 T-cell responses, namely, Abs to the CD4-binding domain (CD4bd) of gp120 (17,18). In the presence of these Abs, CD4 T-cell responses to various gp120 epitopes, including those distant from the CD4bd, are prevented.…”

“…These Abs do not affect the CD4 T cell directly and do not alter the overall functions of the antigen-presenting cells (APCs), as evidenced by the fact that T-cell responses to other antigens of HIV-1, mycobacteria, and cytomegalovirus are not diminished in the presence of anti-CD4bd Abs (17,18). Notably, formation of the gp120/anti-CD4bd Ab complexes is essential for the inhibitory activity, and the complexes must be present during antigen pulsing of APCs (18), indicating that these Abs, when forming complexes with gp120, affect gp120 antigen uptake or processing by APCs for subsequent major histocompatibility complex (MHC) class II presentation to cognate CD4 T cells. The capacity of Abs to alter antigen processing has been well documented in the literature.…”

Role of Neutralizing Antibodies in Protective Immunity Against HIV

“…[71][72][73] It is interesting to note that no other antibodies to other epitopes on gp120, 71 and not all CD4 BS mAbs display this phenomenon. It has been shown by Herrera and colleagues (2003) that neutralizing (b12) and non-neutralizing antibodies (205-42-15; 204-43-4 and 205-46-9) do compete for binding to gp120 monomer demonstrating the close topological proximity of epitopes recognized by these mAbs.…”