부산대학교 도서관

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 ⍺4β7, 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 ⍺4β7 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 ⍺4β7, 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 β-strand of CD4 D2, KIDIV, that binds directly to ⍺4β7. 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-⍺4β7 binding. The accessory ⍺4β7 binding site on CD4 includes Phe43. The Phe43 aromatic ring protrudes outward from one edge of a loop connecting the C'C" strands of CD4 D1. Phe43 is a principal contact for HIV gp120. It interacts with conserved residues in the recessed CD4 binding pocket. Substitution of Phe43 abrogates CD4 binding to both gp120 and ⍺4β7. As such, the interactions of gp120 with both CD4 and ⍺4β7 reflect elements of their interactions with each other. These findings indicate that gp120 specificities for CD4 and ⍺4β7 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. Author summary: Integrins modulate cell trafficking and provide costimulatory signals to leukocytes. An increasing number have also been shown to interact in cis with immune receptors. Formation of these multi-receptor complexes is dynamic and typically serves a regulatory function. We report a cis interaction between ⍺4β7, the gut-homing integrin and CD4, a receptor that plays a central role in the adaptive immune response. CD4-⍺4β7 interactions share features with MAdCAM-1 and VCAM-1, two natural ligands that engage ⍺4β7 in trans. All three receptors engage ⍺4β7 through two discreet sites distributed across their two N-terminal IgSF domains. Specific features of the two ⍺4β7 binding sites on CD4 are related to HIV pathogenesis in a unique and informative way. HIV gp120 binds to both CD4 and ⍺4β7. A key finding of this report is that specific elements of gp120-CD4 and gp120-⍺4β7 interactions reflect the interaction of these two receptors with each other. We conclude that the selective pressures that resulted in a virus which infects and depletes gut CD4+ T cells are linked to CD4-⍺4β7 cis interactions. [ABSTRACT FROM AUTHOR]