The V2 domain of HIV gp120 mimics an interaction between CD4 and integrin ₄₇

The CD4 receptor, by stabilizing TCR-MHC II interactions, plays a central role in adaptive immunity. It also serves as the HIV docking receptor. The HIV gp120 envelope protein binds directly to CD4. This interaction is a prerequisite for viral entry. gp120 also binds to alpha(4)beta(7), an integrin that is expressed on a subset of memory CD4(+) T cells. HIV tropisms for CD4(+) T cells and gut tissues are central features of HIV pathogenesis. We report that CD4 binds directly to alpha(4)beta(7) in a dynamic way, consistent with a cis regulatory interaction. The molecular details of this interaction are related to the way in which gp120 interacts with both receptors. Like MAdCAM-1 and VCAM-1, two recognized ligands of alpha(4)beta(7), the binding interface on CD4 includes 2 sites (1 degrees and accessory), distributed across its two N-terminal IgSF domains (D1 and D2). The 1 degrees site includes a sequence in the G beta-strand of CD4 D2, KIDIV, that binds directly to alpha(4)beta(7). This pentapeptide sequence occurs infrequently in eukaryotic proteins. However, a closely related and conserved sequence, KLDIV, appears in the V2 domain of gp120. KLDIV mediates gp120-alpha(4)beta(7) binding. The accessory alpha(4)beta(7) binding site on CD4 includes Phe(43). The Phe(43) aromatic ring protrudes outward from one edge of a loop connecting the C'C '' strands of CD4 D1. Phe(43) is a principal contact for HIV gp120. It interacts with conserved residues in the recessed CD4 binding pocket. Substitution of Phe(43) abrogates CD4 binding to both gp120 and alpha(4)beta(7). As such, the interactions of gp120 with both CD4 and alpha(4)beta(7) reflect elements of their interactions with each other. These findings indicate that gp120 specificities for CD4 and alpha(4)beta(7) are interrelated and suggest that selective pressures which produced a CD4 tropic virus that replicates in gut tissues are linked to a dynamic interaction between these two receptors.