Vedolizumab-Mediated Integrin Alpha 4 Beta 7 Blockade Does Not Control Hiv-1(Sf162) Rebound After Combination Antiretroviral Therapy Interruption In Humanized Mice

Objective: The combined combination antiretroviral therapy (cART) and anti-alpha 4 beta 7 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-alpha 4 beta 7 antibody, would have similar effects in controlling live HIV-1 infection in humanized mice.Design and methods: The integrin alpha 4 beta 7 blockade by VDZ was evaluated on human primary memory CD+ T (T-MEM) cells and retinoic acid-induced gut-homing alpha 4 beta 7(MEM)(+)T cells alpha 4 beta 7(MEM)(+)T) in vitro. The antiretroviral activity of VDZ was determined using pseudotyped R5-tropic HIV-1(SF162), which displays binding activity to alpha 4 beta 7. The preventive and immunotherapeutic efficacies of VDZ were further investigated in humanized mice using the live HIV-1(SF162) 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 alpha 4 beta 7, to alpha 4 beta 7(MEM)(+)T cells. HIV-1(SF162) not only displayed binding capacity to alpha 4 beta 7-expressing cells, but also showed an increased infectivity in retinoic acid-induced alpha 4 beta 7(MEM)(+)T cells pretreated with VDZ. Moreover, VDZ failed to prevent live HIV-1(SF162) 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-1(SF162) rebound in humanized mice, whereas the alpha 4 beta 7 molecules remained significantly blocked on circulating CD4(+) T cells.Conclusion: VDZ neither prevents nor controls HIV-1(SF162) 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. Copyright (C) 2019 Wolters Kluwer Health, Inc. All rights reserved.