The V2 domain of HIV gp120 mimics an interaction between CD4 and integrin âº4ß7.
PLoS Pathog
; 19(12): e1011860, 2023 Dec.
Article
em En
| MEDLINE
| ID: mdl-38064524
ABSTRACT
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 âº4ß7, 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 âº4ß7 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 âº4ß7, 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 ß-strand of CD4 D2, KIDIV, that binds directly to âº4ß7. 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-âº4ß7 binding. The accessory âº4ß7 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 âº4ß7. As such, the interactions of gp120 with both CD4 and âº4ß7 reflect elements of their interactions with each other. These findings indicate that gp120 specificities for CD4 and âº4ß7 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Infecções por HIV
/
Integrinas
Limite:
Humans
Idioma:
En
Revista:
PLoS Pathog
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Estados Unidos