Enhancement of human immunodeficiency virus type 1 envelope-mediated fusion by a CD4-gp120 complex-specific monoclonal antibody
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1Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
Insights
A novel monoclonal antibody, CG10, enhances human immunodeficiency virus type 1 (HIV-1) entry into cells by targeting a conserved CD4-gp120 intermediate structure, facilitating viral fusion and infection.
Area of Science:
- Virology
- Immunology
- Cell Biology
Background:
- Human immunodeficiency virus type 1 (HIV-1) entry into host cells is a complex process initiated by the binding of viral glycoproteins (gp120-gp41) to the cellular receptor CD4.
- This initial binding triggers conformational changes in the viral complex, leading to potential association with other membrane components and eventual cell fusion.
- These structural rearrangements are associated with altered immunological profiles, including changes in reactivity with specific monoclonal antibodies and the emergence of new epitopes.
Purpose of the Study:
- To analyze the structure and function of the CD4-gp120 complex formed during HIV-1 entry.
- To investigate the role of specific monoclonal antibodies in modulating HIV-1 cell fusion and viral entry.
Main Methods:
- Generation of monoclonal antibodies from mice immunized with soluble CD4-gp120 molecules.
- Characterization of a complex-specific monoclonal antibody, CG10, for its ability to bind the CD4-gp120 complex.
- Assays to measure cell-cell fusion mediated by HIV-1 envelopes and viral infection rates in the presence of CG10.
Main Results:
- The monoclonal antibody CG10 specifically recognized the CD4-gp120 complex.
- CG10 significantly enhanced cell fusion mediated by both T-cell-line-tropic and macrophage-tropic HIV-1 envelopes.
- CG10 increased the infection of HeLa CD4+ (MAGI) cells by multiple HIV-1 strains by two- to fourfold, indicating an effect on viral entry.
Conclusions:
- A novel, conserved intermediate structure involving CD4 and gp120 exists during HIV-1 cell entry.
- This CD4-gp120 intermediate plays a crucial role in the fusion process.
- Monoclonal antibody CG10 provides a tool to probe and enhance this critical step in HIV-1 infection.
Abstract:
The entry of human immunodeficiency virus type 1 (HIV-1) into cells is initiated by binding of the viral glycoprotein gp120-gp41 to its cellular receptor CD4. The gp120-CD4 complex formed at the cell surface undergoes conformational changes that may allow its association with an additional membrane component(s) and the eventual formation of the fusion complex. These conformational rearrangements are accompanied by immunological changes manifested by altered reactivity with monoclonal antibodies specific for the individual components and presentation of new epitopes unique to the postbinding complex. In order to analyze the structure and function of the gp120-CD4 complex, monoclonal antibodies were generated from splenocytes of BALB/c mice immunized with soluble CD4-gp120 (IIIB) molecules (J. M. Gershoni, G. Denisova, D. Raviv, N. I. Smorodinsky, and D. Buyaner, FASEB J. 7:1185-1187 1993). One of those monoclonal antibodies, CG10, was found to be strictly complex specific. Here we demonstrate that this monoclonal antibody can significantly enhance the fusion of CD4+ cells with effector cells expressing multiple HIV-1 envelopes. Both T-cell-line-tropic and macrophage-tropic envelope-mediated cell fusion were enhanced, albeit at different optimal doses. Furthermore, infection of HeLa CD4+ (MAGI) cells by HIV-1 LAI, ELI1, and ELI2 strains was increased two- to fourfold in the presence of CG10 monoclonal antibodies, suggesting an effect on viral entry. These findings indicate the existence of a novel, conserved CD4-gp120 intermediate structure that plays an important role in HIV-1 cell fusion.
