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Article: Vedolizumab-mediated integrin α4β7 blockade does not control HIV-1SF162 rebound after combination antiretroviral therapy interruption in humanized mice

TitleVedolizumab-mediated integrin α4β7 blockade does not control HIV-1SF162 rebound after combination antiretroviral therapy interruption in humanized mice
Authors
Issue Date2019
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://www.AIDSonline.com
Citation
AIDS, 2019, v. 33 n. 4, p. F1-F12 How to Cite?
AbstractObjective: 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. Design and methods: 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. Results: 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. 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.
Persistent Identifierhttp://hdl.handle.net/10722/272054
ISSN
2017 Impact Factor: 4.914
2015 SCImago Journal Rankings: 3.112

 

DC FieldValueLanguage
dc.contributor.authorLing, L-
dc.contributor.authorWu, T-
dc.contributor.authorTo, KKW-
dc.contributor.authorCheung, KW-
dc.contributor.authorLui, KOL-
dc.contributor.authorNiu, M-
dc.contributor.authorLam, KS-
dc.contributor.authorWang, CC-
dc.contributor.authorLi, J-
dc.contributor.authorWang, H-
dc.contributor.authorYuen, KY-
dc.contributor.authorChen, Z-
dc.date.accessioned2019-07-20T10:34:45Z-
dc.date.available2019-07-20T10:34:45Z-
dc.date.issued2019-
dc.identifier.citationAIDS, 2019, v. 33 n. 4, p. F1-F12-
dc.identifier.issn0269-9370-
dc.identifier.urihttp://hdl.handle.net/10722/272054-
dc.description.abstractObjective: 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. Design and methods: 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. Results: 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. 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.-
dc.languageeng-
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://www.AIDSonline.com-
dc.relation.ispartofAIDS-
dc.titleVedolizumab-mediated integrin α4β7 blockade does not control HIV-1SF162 rebound after combination antiretroviral therapy interruption in humanized mice-
dc.typeArticle-
dc.identifier.emailTo, KKW: kelvinto@hku.hk-
dc.identifier.emailYuen, KY: kyyuen@hkucc.hku.hk-
dc.identifier.emailChen, Z: zchenai@hku.hk-
dc.identifier.authorityTo, KKW=rp01384-
dc.identifier.authorityYuen, KY=rp00366-
dc.identifier.authorityChen, Z=rp00243-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1097/QAD.0000000000002149-
dc.identifier.pmid30829743-
dc.identifier.scopuseid_2-s2.0-85062399602-
dc.identifier.hkuros298709-
dc.identifier.volume33-
dc.identifier.issue4-
dc.identifier.spageF1-
dc.identifier.epageF12-
dc.publisher.placeUnited States-

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