Envelope glycoprotein binding to the integrin α4β7 is not a general property of most HIV-1 strains.

UNLABELLED: The HIV-1 surface glycoprotein gp120 has been reported to bind and signal through α4β7 by means of a tripeptide motif in the V2 loop that mimics structures present in the natural ligands for α4β7, suggesting that α4β7 may facilitate HIV-1 infection of CD4(+) T cells in the gut. Furthermore, immune correlates in the RV144 vaccine efficacy trial generated the hypothesis that V1V2 antibodies to an epitope near the putative α4β7 binding motif may play a role in protection against HIV-1 infection. In the interest of developing an assay to detect antibodies that block gp120 binding to α4β7, we used retinoic acid (RA)-activated human peripheral blood mononuclear cells (PBMCs) and transfected HEK293T (293T) cells expressing the integrin complex to study the α4β7 binding properties of 16 HIV-1 envelope glycoproteins. The natural ligand for α4β7, mucosal addressin cell adhesion molecule-1 (MAdCAM-1), bound efficiently to RA-activated PBMCs and transfected 293T cells, and this binding was blocked by antibodies to α4. gp120 from multiple HIV-1 subtypes bound to RA-activated PBMCs from three donors in a CD4-dependent manner, but little or no α4β7 binding was detected. Similarly, little or no binding to α4β7 on transfected 293T cells was detected with multiple gp120s and gp140s, including gp120s from transmitted/founder strains, or when gp120 was produced in CHO, 293T, and 293S/GnT1(-/-) cells. Finally, we found no evidence that infectious HIV-1 virions produced in either PBMCs or 293T cells could bind α4β7 on transfected 293T cells. Infectious HIV-1 virions and most gp120s/gp140s appear to be poor ligands for the α4β7 integrin complex under the conditions tested here. IMPORTANCE: Certain HIV-1 gp120 envelope glycoproteins have been shown to bind the gut-homing receptor α4β7, and it has been suggested that this binding facilitates mucosal transmission and virus replication in the gut mucosa. Additional evidence has generated the hypothesis that antibodies that bind near the putative α4β7 binding motif in the V2 loop of gp120, possibly disrupting gp120-α4β7 binding, may be important for HIV-1 vaccines. Our evidence indicates that infectious HIV-1 virions and many gp120s lack detectable α4β7 binding activity, suggesting that this homing receptor may play a limited role in direct HIV-1 infection of cells.