Computational Modeling of pH Sensitivity in the Critical HIV gp120-CD4 Interaction

Abstract

Although acquired immune deficiency syndrome (AIDS) was discovered more than thirty years ago, an effective vaccine against the human immunodeficiency virus (HIV) that causes the disease has not yet been produced. This is potentially because most HIV vaccine research has been performed under slightly basic, systemic blood/plasma conditions, while transmission events often occur under highly acidic, mucosal conditions. Furthermore, the gp120 envelope protein, which initiates transmission via binding to host cell receptor CD4, has been shown to more effectively bind CD4 under acidic conditions presumably due to favorable, pH sensitive conformational changes. We have used computational modeling to compute the strength of the gp120-CD4 interaction for a variety of gp120 sequences over a physiologically relevant range of pH values, and found that the interaction is strongest at low, mucosal level pH. We also compared the pH sensitivity of this interaction between early infection transmission/founder (TF) strains, and chronic control (CC) strains which circulate systemically post-transmission. We found that the gp120-CD4 interaction was more pH sensitive in TF strains, suggesting a different binding mechanism between TFs and CCs. To investigate these differences, we mapped sequence specific pH sensitivity onto the binding site of the solved gp120 structure 1RZK to test for residue specific pH sensitivity differences. Residues with significantly different sensitivities between TF and CC strains were used to identify structural differences that are likely to contribute to the difference in pH sensitivity of the gp120-CD4 interaction.