Lack of therapeutic efficacy of an antibody to α
            <sub>4</sub>
            β
            <sub>7</sub>
            in SIVmac251-infected rhesus macaques

Abbink, Peter; Mercado, Noe B.; Nkolola, Joseph P.; Peterson, Rebecca; Tuyishime, Hubert; McMahan, Katherine; Moseley, Edward T.; Borducchi, Erica N.; Chandrashekar, Abishek; Bondzie, Esther A.; Agarwal, Arshi; Belli, Aaron J.; Reimann, Keith A.; Keele, Brandon F.; Geleziunas, Romas; Lewis, Mark G.; Barouch, Dan H.

doi:10.1126/science.aaw8562

Cited by 26 publications

(42 citation statements)

References 18 publications

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“…The effect of anti-α4β7 mAb administered in SIVinfected RMs during ART continues to be a highly debatable issue. While an earlier study showed that this treatment can limit viral rebound after ART interruption (21), more recent pre-clinical (23)(24)(25) and clinical (41) studies did not show any significant benefit from anti-α4β7 mAb treatment in ARTsuppressed, HIV-infected individuals or SIV-infected RMs in inducing viral remission in the absence of ART (42). Recently, using samples obtained from various gastrointestinal sites from IBD/CD patients, it was found that anti-α4β7 therapy led to a significant reduction of lymphoid aggregates, mostly in the terminal ileum (43).…”

Section: Discussionmentioning

confidence: 99%

“…IL-21 and anti-α4β7 mAbs have been previously administered as single interventions in naive or SIV-infected RMs with an acceptable safety profile (10,18,(21)(22)(23)(24)(25). However, combined administration of the two reagents has not yet been tested.…”

Section: The Combined Administration Of Il-21 and Anti-α4β7 Mab Is Samentioning

confidence: 99%

“…Previous studies have shown that the administration of anti-α4β7 mAb can lead to the development of ADA in a subset of RMs, which resulted in loss of anti-α4β7 mAb biological activity (21,23,24). In one of those studies, in which 11 RMs received eight intravenously doses of the anti-α4β7 mAb (50 mg/kg each; at weeks 9, 12, 16, 18, 20, 24, 28, and 32 post-SIV infection), three animals developed ADA responses starting either after two, three, or six doses (21).…”

Section: Co-administration Of Il-21 and Anti-α4β7 Mab Does Not Inducementioning

confidence: 99%

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Safety and Immunological Evaluation of Interleukin-21 Plus Anti-α4β7 mAb Combination Therapy in Rhesus Macaques

et al. 2020

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Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections compromise gut immunological barriers, inducing high levels of inflammation and a severe depletion of intestinal CD4 + T cells. Expression of α4β7 integrin promotes homing of activated T cells to intestinal sites where they become preferentially infected; blockade of α4β7 with an anti-α4β7 monoclonal antibody (mAb) prior to infection has been reported to reduce gut SIV viremia in rhesus macaques (RMs). Interleukin-21 (IL-21) administration in antiretroviral therapy-treated, SIV-infected RMs reduces gut inflammation and improves gut integrity. We therefore hypothesized that the combination of IL-21 and anti-α4β7 mAb therapies could synergize to reduce inflammation and HIV persistence. We co-administered two intravenous doses of rhesus anti-α4β7 mAb (50 mg/kg) combined with seven weekly subcutaneous infusions of IL-21-IgFc (100 µg/kg) in four healthy, SIV-uninfected RMs to evaluate the safety and immunological profiles of this intervention in blood and gut. Co-administration of IL-21 and anti-α4β7 mAb showed no toxicity at the given dosages as assessed by multiple hematological and chemical parameters and did not alter the bioavailability of the therapeutics or result in the generation of antibodies against the anti-α4β7 mAb or IL-21-IgFc. Upon treatment, the frequency of CD4 memory T cells expressing β7 increased in blood and decreased in gut, consistent with an inhibition of activated CD4 T-cell homing to the gut. Furthermore, the frequency of T cells expressing proliferation and immune activation markers decreased in blood and, more profoundly, in gut. The combined IL-21 plus anti-α4β7 mAb therapy is well-tolerated in SIV-uninfected RMs and reduces the gut homing of α4β7 + CD4 T cells as well as the levels of gut immune activation.

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Section: Discussionmentioning

confidence: 99%

Section: The Combined Administration Of Il-21 and Anti-α4β7 Mab Is Samentioning

confidence: 99%

Section: Co-administration Of Il-21 and Anti-α4β7 Mab Does Not Inducementioning

confidence: 99%

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Safety and Immunological Evaluation of Interleukin-21 Plus Anti-α4β7 mAb Combination Therapy in Rhesus Macaques

et al. 2020

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“…Blocking of α4β7 in monkey models showed promise for prevention of SIV infection and for viral control in SIV-infected monkeys [39,40]. However, the latter results were not substantiated in recent studies of nonhuman primates [41][42][43] or HIV-infected patients [44].…”

Section: Expression Of Lfa-1 Integrin On Cd4+ T Cells Promotes Hiv Enmentioning

confidence: 97%

Endothelial cells promote productive HIV infection of resting CD4+ T cells by an integrin-mediated cell adhesion-dependent mechanism

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Abrenica

McKinnon

et al. 2020

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AbstractResting CD4+ T cells do not support HIV replication in vitro, yet are primary targets of early HIV infection events in vivo. There is an established role for factors in the tissue microenvironment, including endothelial cells, in enhancing the susceptibility of resting CD4+ T cells to productive infection, yet the mechanisms behind this are not well understood. Endothelial cells facilitate immune cell trafficking throughout the body. Cell adhesion molecules expressed by endothelial cells engage integrins on activated and memory T cells and mediate transmigration into inflamed tissues. These cell trafficking pathways have overlapping roles in facilitating HIV replication but their relevance to endothelial cell-mediated enhancement of HIV susceptibility in resting CD4+ T cells has not previously been examined. We used flow cytometry to characterize the phenotype resting CD4+ T cells that became productively infected when exposed to HIV in the presence of endothelial cells. Infected CD4+ T cells were primarily central memory cells enriched for high expression of the integrins LFA-1 and VLA-4 and had variable expression of α4β7, CCR6 and CD69. Blocking LFA-1 and VLA-4 on resting CD4+ T cells abrogated infection in the co-culture model, indicating that engagement of these integrins is essential for enhancement of resting CD4+ T cell HIV susceptibility by endothelial cells. Cellular activation of CD4+ T cells did not appear to be the primary mechanism enabling HIV replication since only a small proportion of resting CD4+ T cells became activated over the course of the co-culture and fewer than half of infected cells had an activated phenotype. The demonstration that endothelial cells enhance the cellular HIV susceptibility of resting memory CD4+ T cells through cell trafficking pathways engaged during the transmigration of memory T cells into inflamed tissues highlights the physiological relevance of these findings for HIV acquisition and opportunities for intervention.Author SummaryHIV acquisition risk per coital act is relatively low, but this risk is amplified by various behavioural and biological variables. Genital inflammation is a key biological variable associated with increased risk of HIV acquisition, but the mechanisms driving this are incompletely understood. Inflammation is a complex process, with direct effects on HIV target cells as well as the tissue in which those cells reside and encounter virus. The first HIV target cells in vivo are resting memory CD4+ T cells, yet these cells are do not support viral replication when purified and exposed to HIV in vitro. Rather, signals from tissue microenvironment are required to support viral replication within resting memory CD4+ T cells. Endothelial cells line tissue vasculature and guide immune cell trafficking to inflamed tissues through engagement of integrins by endothelial-expressed cell adhesion molecules. We show here that these same cell-trafficking pathways enable endothelial cells to promote HIV replication within resting memory CD4+ T cells in vitro. Blockade of integrins on resting memory CD4+ T cells prevented endothelial enhancement of HIV infection. These findings further our understanding of the determinants of cellular susceptibility to HIV infection and offer a potential mechanism by which inflammation promotes HIV acquisition.

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“…(3) have received ART for between 2 and 10 years; (4) have no other significant comorbidity; (5) are receiving no other immune-modulating treatments; (6) have wellcontrolled HIV infection as defined by stable pVL of <50 copies/mL and CD4 counts >500 cells/µL with nadir CD4 counts >200 cells/µL. Adults may be male, female or transgender.…”

Section: Inclusion Criteriamentioning

confidence: 99%

Vedolizumab treatment across antiretroviral treatment interruption in chronic HIV infection: the HAVARTI protocol for a pilot dose-ranging clinical trial to assess safety, tolerance, immunological and virological activity

et al. 2020

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IntroductionContinuous antiretroviral therapy (ART) suppresses HIV plasma viral load (pVL) to very low levels, which allows for some immune recovery. Discontinuation of ART leads to pVL rebound from reservoirs of persistence and latency, and progressive immunodeficiency. One promising but controversial strategy targeting CD4+ T lymphocytes with a monoclonal antibody (mAb) against α4β7 integrin has shown promise through sustained virological remission of pVL (SVR) in SIV239-infected rhesus macaques. We propose to assess the safety and tolerability of vedolizumab, a licensed humanised mAb against human α4β7 integrin, in healthy HIV-infected adults on ART. This study will also assess, by analytical treatment interruption (ATI), whether vedolizumab treatment can induce SVR beyond ART and vedolizumab treatment.Methods and analysisThe HIV-ART-vedolizumab-ATI (HAVARTI) trial is a single-arm, dose-ranging pilot trial in healthy HIV-positive adult volunteers receiving ART. Twelve consenting persons will be enrolled in sequential groups of 4 to each serial dosing vedolizumab regimen (300 mg, 150 mg, 75 mg). The primary outcomes are: (1) to assess the safety and tolerability of seven serial infusions of vedolizumab at each of three doses; (2) to identify the immunovirological measures, including pVL and T-cell kinetics, that characterise HIV/ART cases before, during, after vedolizumab treatment and ATI; and (3) to seek SVR of pVL after ATI. Secondary outcomes will include immune reconstitution and pVL suppression as well as immune reconstitution and long-term safety following re-initiation of ART in the absence of SVR.Ethics and disseminationThe study protocol was approved by the Ottawa Health Science Network-REB and by the Health Canada Therapeutic Products Directorate. A Data Safety Monitor will review safety information at regular intervals. The final manuscript will be submitted to an open access journal within a year of study completion.Trial registration numberClinicalTrials.gov NCT03147859; https://clinicaltrials.gov/ct2/show/NCT03147859

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Lack of therapeutic efficacy of an antibody to α ₄ β ₇ in SIVmac251-infected rhesus macaques

Cited by 26 publications

References 18 publications

Safety and Immunological Evaluation of Interleukin-21 Plus Anti-α4β7 mAb Combination Therapy in Rhesus Macaques

Safety and Immunological Evaluation of Interleukin-21 Plus Anti-α4β7 mAb Combination Therapy in Rhesus Macaques

Endothelial cells promote productive HIV infection of resting CD4+ T cells by an integrin-mediated cell adhesion-dependent mechanism

Vedolizumab treatment across antiretroviral treatment interruption in chronic HIV infection: the HAVARTI protocol for a pilot dose-ranging clinical trial to assess safety, tolerance, immunological and virological activity

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Lack of therapeutic efficacy of an antibody to α 4 β 7 in SIVmac251-infected rhesus macaques

Cited by 26 publications

References 18 publications

Safety and Immunological Evaluation of Interleukin-21 Plus Anti-α4β7 mAb Combination Therapy in Rhesus Macaques

Safety and Immunological Evaluation of Interleukin-21 Plus Anti-α4β7 mAb Combination Therapy in Rhesus Macaques

Endothelial cells promote productive HIV infection of resting CD4+ T cells by an integrin-mediated cell adhesion-dependent mechanism

Vedolizumab treatment across antiretroviral treatment interruption in chronic HIV infection: the HAVARTI protocol for a pilot dose-ranging clinical trial to assess safety, tolerance, immunological and virological activity

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Product

Resources

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Lack of therapeutic efficacy of an antibody to α ₄ β ₇ in SIVmac251-infected rhesus macaques