Extracellular Matrix Proteins Mediate HIV-1 gp120 Interactions with α₄β₇

Area of Science:

• Immunology and Virology
• Cellular and Molecular Biology

Background:

• Human immunodeficiency virus type 1 (HIV-1) preferentially targets gut-homing α4β7high CD4+ T lymphocytes, contributing to pathogenesis.
• HIV-1 envelope protein gp120 binding and signaling through α4β7 are implicated in T cell infection and virus transmission.
• Previous studies suggested specific gp120 V2 loop motifs mediate α4β7 binding, but results were inconsistent.

Purpose of the Study:

• To investigate the precise determinants of gp120-α4β7 binding, addressing inconsistencies in previous findings.
• To explore the role of extracellular matrix proteins in mediating gp120-α4β7 interactions.

Main Methods:

• Co-purification of extracellular matrix proteins, including fibronectin, with recombinant gp120 expressed in Chinese hamster ovary (CHO) cells.
• In vitro cell binding assays using CHO cell fibronectin and recombinant human fibronectin fragments to assess gp120-α4β7 interactions.
• Anion-exchange chromatography to remove fibronectin and evaluate its role in gp120-α4β7 binding.
• Antibody blocking assays targeting the gp120 V2 loop.

Main Results:

• Fibronectins from CHO cells mediated binding of diverse gp120 proteins to α4β7, independent of the gp120 V2 loop.
• Removal of fibronectin abrogated V2-independent gp120-α4β7 binding.
• A recombinant human fibronectin fragment replicated the gp120-α4β7 interaction mediated by CHO cell fibronectin.

Conclusions:

• Fibronectin and potentially other extracellular matrix proteins mediate indirect gp120-α4β7 interactions, explaining previously contradictory findings.
• The gp120 V2 loop is not essential for fibronectin-mediated binding to α4β7.
• These findings reveal a novel mechanism in HIV-1-host cell interactions and suggest extracellular matrix proteins as potential therapeutic targets.