Envelope Glycoprotein Binding to the Integrin α4β7 Is Not a General Property of Most HIV-1 Strains

The HIV-1 surface glycoprotein gp120 has been reported to bind and signal through alpha(4)beta(7) by means of a tripeptide motif in the V2 loop that mimics structures present in the natural ligands for alpha(4)beta(7), suggesting that alpha(4)beta(7) 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 alpha(4)beta(7) 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 alpha(4)beta(7), we used retinoic acid (RA)-activated human peripheral blood mononuclear cells (PBMCs) and transfected HEK293T (293T) cells expressing the integrin complex to study the alpha(4)beta(7) binding properties of 16 HIV-1 envelope glycoproteins. The natural ligand for alpha(4)beta(7), 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 alpha(4). gp120 from multiple HIV-1 subtypes bound to RA-activated PBMCs from three donors in a CD4-dependent manner, but little or no alpha(4)beta(7) binding was detected. Similarly, little or no binding to alpha(4)beta(7) 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 alpha(4)beta(7) on transfected 293T cells. Infectious HIV-1 virions and most gp120s/gp140s appear to be poor ligands for the alpha(4)beta(7) integrin complex under the conditions tested here. IMPORTANCE Certain HIV-1 gp120 envelope glycoproteins have been shown to bind the gut-homing receptor alpha(4)beta(7), 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 alpha(4)beta(7) binding motif in the V2 loop of gp120, possibly disrupting gp120-alpha(4)beta(7) binding, may be important for HIV-1 vaccines. Our evidence indicates that infectious HIV-1 virions and many gp120s lack detectable alpha(4)beta(7) binding activity, suggesting that this homing receptor may play a limited role in direct HIV-1 infection of cells.