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HLA class II antigens and the HIV envelope glycoprotein gp120 bind to the same face of CD4
R Houlgatte1, P Scarmato, S el Marhomy
1Unité de Génétique Moléculaire et de Biologie du Développement UPR 420, Centre National de la Recherche Scientifique, Villejuif, France.
Insights
The CD4 protein
Area of Science:
- Immunology
- Molecular Biology
- Virology
Background:
- The binding site of CD4 for HIV gp120 is known, but its interaction site with HLA class II molecules remains unclear.
- Understanding CD4 interactions is crucial for HIV research and immunology.
Purpose of the Study:
- To investigate the interaction site of CD4 with HLA class II molecules.
- To determine if the HIV gp120 binding site on CD4 overlaps with the HLA class II binding site.
Main Methods:
- Sixty-seven mutations were introduced into the extracellular domains of CD4.
- Assays included cell surface expression, conformational changes, B lymphocyte adhesion, and HIV gp120 binding.
- Molecular modeling was used to analyze mutation effects.
Main Results:
- Mutations in the gp120 binding site affected both HLA class II adhesion and HIV gp120 binding, suggesting site overlap.
- Additional mutations on the same face of CD4 domains 1 and 2 reduced cell adhesion.
- Molecular modeling indicated these changes resulted from conformational alterations.
Conclusions:
- CD4 primarily interacts with HLA class II molecules via its HIV gp120 binding site.
- A secondary, minor interaction site may exist on the same face of CD4 domains 1 and 2.
- These findings clarify CD4's role in immune interactions and HIV binding.
Abstract:
Although the HIV gp120 binding site of CD4 is well characterized, its interaction site with HLA class II molecules is still controversial. Sixty-seven mutations within the four extracellular domains of CD4 were examined for their effects on cell surface expression and conformational changes and for adhesion of HLA class II-expressing B lymphocytes and HIV gp120 binding to CD4-transfected COS cells. Mutations within the gp120 binding site affected both assays similarly, indicating that the two sites fully overlap. A few additional substitutions of residues mapping on the same face of domains 1 and 2 induced decreased rosette formation. Molecular modeling studies indicated that this is likely to be the consequence of conformational changes induced by the mutations. Thus, CD4 appears to interact with HLA class II molecules mainly through the HIV gp120 binding site and possibly through a second minor interaction site mapping on the same face of the molecule.