Characterization of CD4 glycoprotein determinant-HIV envelope protein interactions: perspectives for analog and vaccine development.

The CD4 surface determinant, previously associated as a phenotypic marker for helper/inducer subsets of T lymphocytes, has now been critically identified as the binding/entry protein for human immunodeficiency viruses (HIV). The human CD4 molecule is readily detectable on monocytes, T lymphocytes, and brain tissues. Soluble HIV (HTLV IIIB) envelope protein (gp120) binds native or recombinant CD4 with equal affinity estimated to be 4 to 8 nM kDa. All human tissue sources of CD4 bind radiolabeled gp120 to the same relative degree; however, the murine homologous protein, L3T4, does not bind the HIV envelope protein. Lack of sufficient recognition by the recombinant L3T4 molecule suggests divergence in the gp120-binding epitope. The binding of gp120 to CD4 is dependent upon intact sulfhydryl bonds within cysteine residues and glycosylation. Deglycosylated native gp120 is unable to bind CD4 under physiological conditions. Recombinant deglycosylated fragments cannot bind to the CD4 receptor, although they serve as immunogen for neutralizing antibody development. A number of synthetic peptides to putative critical domains of gp120 have been studied for their antagonism of native gp120 binding. Peptide T analogs or synthetic cogeners of Neuroleukin proposed to bind the CD4 determinant involved in gp120 binding had no competitive displacement of native gp120 binding as assessed by two independent methods that measure gp120 interaction with CD4. Recombinant C-terminal fragments, also containing other putative domains, did not displace native gp120 from CD4. Glycosylation appears to be critical in the maintenance of the structure of the binding domain of gp120. Native gp120 binding to CD4 is sufficient for the activation of cellular metabolism that alters target cell gene expression and differentiation, suggesting that the virus binding contributes to the activation of the host cell.