Class II MHC molecules and the HIV gp 120 envelope protein interact with functionally distinct regions of the CD4 molecule

A murine T cell hybridoma with a receptor specific for the class I molecule H‐2 Dd was transfected with an expressible cDNA for human CD4. Expression of the human class II MHC molecule HLA‐DP on Dd‐positive murine fibroblasts resulted in a greatly enhanced response of the CD4‐positive T cell hybridoma, measured either by lymphokine production or by rosette formation. Inhibition of these functional assays with anti‐CD4 monoclonal antibodies implicated the two amino‐terminal domains of CD4 in an interaction with the HLA‐DP molecule. This interaction was blocked by incubation with recombinant gp120 envelope protein of HIV. In contrast, recombinant soluble CD4 did not inhibit and was able to prevent the inhibition by gp120. Anti‐CD4 antibody blocking experiments clearly indicated that distinct regions of CD4 interact respectively with gp120 and with class II MHC molecules.