Vedolizumab-mediated integrin 4β7 blockade does not control HIV-1SF162 rebound after combination antiretroviral therapy interruption in humanized mice

The combined combination antiretroviral therapy (cART) and anti-4β7 RM-Act-1 antibody therapy allows macaques to durably control simian immunodeficiency virus (SIV) rebound after withdrawal of the interventions. Here, we aimed to investigate whether vedolizumab (VDZ), a clinical-grade humanized anti-4β7 antibody, would have similar effects in controlling live HIV-1 infection in humanized mice.Design and methods:The integrin 4β7 blockade by VDZ was evaluated on human primary memory CD4 T (MEM T) cells and retinoic acid-induced gut-homing 4β7MEM T cells (4β7MEM T) in vitro. The antiretroviral activity of VDZ was determined using pseudotyped R5-tropic HIV-1SF162 , which displays binding activity to 4β7. The preventive and immunotherapeutic efficacies of VDZ were further investigated in humanized mice using the live HIV-1SF162 strain compared with RM-Act-1.Results:VDZ effectively and dose-dependently blocked the binding of mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1), the native ligand of 4β7, to 4β7MEM T cells. HIV-1SF162 not only displayed binding capacity to 4β7-expressing cells, but also showed an increased infectivity in retinoic acid-induced 4β7MEM T cells pretreated with VDZ. Moreover, VDZ failed to prevent live HIV-1SF162 infection and did not reduce the peak viral load when administrated prior to viral challenge in humanized mice. Lastly, in immunotherapeutic settings, the withdrawal of combined cART with either VDZ or RM-Act-1 resulted in an uncontrolled HIV-1SF162 rebound in humanized mice, whereas the 4β7 molecules remained significantly blocked on circulating CD4 T cells.Conclusion:VDZ neither prevents nor controls HIV-1SF162 infection both in vitro and in humanized mice. Our findings have significant implications to the clinical application of VDZ in HIV-1 preventive and immunotherapeutic interventions.