The V2 domain of HIV gp120 mimics an interaction between CD4 and integrin âº.sub.4[beta].sub.7

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 âº.sub.4 [beta].sub.7, an integrin that is expressed on a subset of memory CD4.sup.+ T cells. HIV tropisms for CD4.sup.+ T cells and gut tissues are central features of HIV pathogenesis. We report that CD4 binds directly to âº.sub.4 [beta].sub.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 âº.sub.4 [beta].sub.7, the binding interface on CD4 includes 2 sites (1° and accessory), distributed across its two N-terminal IgSF domains (D1 and D2). The 1° site includes a sequence in the G [beta]-strand of CD4 D2, KIDIV, that binds directly to âº.sub.4 [beta].sub.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-âº.sub.4 [beta].sub.7 binding. The accessory âº.sub.4 [beta].sub.7 binding site on CD4 includes Phe.sup.43 . The Phe.sup.43 aromatic ring protrudes outward from one edge of a loop connecting the C'C" strands of CD4 D1. Phe.sup.43 is a principal contact for HIV gp120. It interacts with conserved residues in the recessed CD4 binding pocket. Substitution of Phe.sup.43 abrogates CD4 binding to both gp120 and âº.sub.4 [beta].sub.7 . As such, the interactions of gp120 with both CD4 and âº.sub.4 [beta].sub.7 reflect elements of their interactions with each other. These findings indicate that gp120 specificities for CD4 and âº.sub.4 [beta].sub.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.