Vedolizumab-mediated integrin α4β7 blockade does not control HIV-1SF162 rebound after combination antiretroviral therapy interruption in humanized mice
| Autor: | Zhiwei Chen, Lijun Ling, Mengyue Niu, Kelvin K. W. To, Kathy O. Lui, Ka Shing Lam, Hui Wang, Kwok-Yung Yuen, Jiatao Li, Chi Chi Wang, Tongjin Wu, Ka-Wai Cheung |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cart CD4-Positive T-Lymphocytes Integrins viruses Immunology Integrin Human immunodeficiency virus (HIV) HIV Infections Mice SCID medicine.disease_cause Antibodies Monoclonal Humanized Vedolizumab 03 medical and health sciences 0302 clinical medicine Antiretroviral Therapy Highly Active medicine Immunology and Allergy Animals Humans Immunologic Factors 030212 general & internal medicine Cells Cultured biology business.industry Simian immunodeficiency virus Viral Load Antiretroviral therapy Blockade 030104 developmental biology Infectious Diseases Treatment Outcome Anti-Retroviral Agents biology.protein HIV-1 business Antibody therapy medicine.drug |
| Zdroj: | AIDS (London, England). 33(4) |
| ISSN: | 1473-5571 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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