The combined combination antiretroviral therapy (cART) and anti-α4β7 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-α4β7 antibody, would have similar effects in controlling live HIV-1 infection in humanized mice.
The integrin α4β7 blockade by VDZ was evaluated on human primary memory CD4+ T (MEMT) cells and retinoic acid-induced gut-homing α4β7+ MEMT cells (α4β7+ MEMT) in vitro. The antiretroviral activity of VDZ was determined using pseudotyped R5-tropic HIV-1SF162, which displays binding activity to α4β7. The preventive and immunotherapeutic efficacies of VDZ were further investigated in humanized mice using the live HIV-1SF162 strain compared with RM-Act-1.
VDZ effectively and dose-dependently blocked the binding of mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1), the native ligand of α4β7, to α4β7+ MEMT cells. HIV-1SF162 not only displayed binding capacity to α4β7-expressing cells, but also showed an increased infectivity in retinoic acid-induced α4β7+ MEMT 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 α4β7 molecules remained significantly blocked on circulating CD4+ T cells.
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.
aAIDS Institute and Department of Microbiology, State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region
bHKU-AIDS Institute Shenzhen Research Laboratory, Guangdong Key Laboratory of Emerging Infectious Diseases and Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People's Hospital, Shenzhen
cDepartment of Chemical Pathology, Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
dDepartment of Obstetrics and Gynaecology, Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China.
Correspondence to Zhiwei Chen, AIDS Institute and Department of Microbiology, State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, L5-44, Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong Special Administrative Region, People's Republic of China. E-mail: firstname.lastname@example.org
Received 4 April, 2018
Revised 22 December, 2018
Accepted 8 January, 2019
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