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Synergism between HIV gp120 and gp120-specific antibody in blocking human T cell activation
1Bristol-Myers Company, Wallingford, CT 06492.
Insights
Human immunodeficiency virus (HIV) envelope protein gp120 binds CD4+ cells. HIV gp120 and gp120-specific antibodies synergistically inhibit T cell activation by targeting CD4 molecules.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- Human immunodeficiency virus (HIV) infects CD4-positive cells via its envelope glycoprotein (gp120) binding to the CD4 molecule.
- CD4 is a key immunoregulatory molecule; antibodies against CD4 (anti-CD4) induce immunodeficiency and inhibit T cell responses.
- Understanding HIV-CD4 interactions is crucial for developing therapeutic strategies.
Purpose of the Study:
- To investigate the mechanism by which HIV gp120 and gp120-specific antibodies affect T cell activation.
- To determine if antibodies from HIV-seropositive individuals can target CD4 molecules in the presence of gp120.
- To elucidate the role of trimolecular complex formation in T cell suppression.
Main Methods:
- Experimental analysis of trimolecular complex formation between CD4, HIV gp120, and gp120-specific antibodies.
- Assessment of T cell activation by measuring intracellular calcium (Ca2i+) mobilization.
- In vitro studies evaluating the effects of gp120 and anti-gp120 antibodies on T cell responses.
Main Results:
- CD4-bound gp120 attracts gp120-specific antibodies from HIV-seropositive individuals, forming a trimolecular complex.
- This complex formation causes gp120-specific antibodies to function as anti-CD4 antibodies, cross-linking and modulating CD4 molecules.
- Synergistic suppression of T cell activation was observed at low concentrations of both gp120 and anti-gp120; neither component alone inhibited T cell activation.
Conclusions:
- HIV gp120 facilitates the targeting of CD4 molecules by gp120-specific antibodies, mimicking the effects of anti-CD4 antibodies.
- The formation of a trimolecular complex is a key mechanism for suppressing T cell activation in HIV infection.
- This interaction highlights a potential pathway for HIV-induced immunodeficiency and suggests therapeutic targets.
Abstract:
The human immunodeficiency virus (HIV) binds to CD4-positive cells through interaction of its envelope glycoprotein (gp120) with the CD4 molecule. CD4 is a prominent immunoregulatory molecule, and chronic exposure to antibody against CD4 (anti-CD4) has been shown to cause immunodeficiency in mice. T cell-dependent in vitro immune responses can also be inhibited by anti-CD4. Experimental findings reported here indicate that CD4-bound gp120 attracts gp120-specific antibodies derived from the blood of HIV-seropositive individuals to form a trimolecular complex with itself and CD4. Thus targeted to CD4, the gp120-specific antibody functions as an antibody to CD4; it cross-links and modulates the CD4 molecules and suppresses the activation of T cells as measured by mobilization of intracellular calcium (Ca2i+). The synergism between gp120 and anti-gp120 in blocking T cell activation occurs at low concentrations of both components. Neither gp120 nor anti-gp120 inhibits T cell activation by itself in the concentrations tested.
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