Blocking α
            <sub>4</sub>
            β
            <sub>7</sub>
            integrin binding to SIV does not improve virologic control

Iwamoto, Nobuya; Mason, Rosemarie D.; Song, Ki Duk; Gorman, Jason; Welles, Hugh C.; Arthos, James; Cicala, Claudia; Min, Susie; King, Hannah A. D.; Belli, Aaron J.; Reimann, Keith A.; Foulds, Kathryn E.; Kwong, Peter D.; Lifson, Jeffrey D.; Keele, Brandon F.; Roederer, Mario

doi:10.1126/science.aaw7765

Cited by 26 publications

(35 citation statements)

References 22 publications

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“…the likelihood of α 4 β 7 integrin binding motif-directed V2-specific antibody binding. In nonhuman primates targeting α 4 β 7 integrin with a primatized mAb protected animals from repeated low-dose intravaginal SIV challenge (36)(37)(38), but a follow-up SIV infection study found that the same antibody had no effect on virological control (39). Blocking Env-α 4 β 7 integrin in vitro did not inhibit CD4 + T cell infection (40).…”

Section: Discussionmentioning

confidence: 99%

HIV vaccine delayed boosting increases Env variable region 2–specific antibody effector functions

Easterhoff¹,

Pollara²,

Luo³

et al. 2020

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Section: Discussionmentioning

confidence: 99%

HIV vaccine delayed boosting increases Env variable region 2–specific antibody effector functions

Easterhoff¹,

Pollara²,

Luo³

et al. 2020

JCI Insight

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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%

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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“…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

Card

Abrenica

McKinnon

et al. 2020

Preprint

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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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Blocking α ₄ β ₇ integrin binding to SIV does not improve virologic control

Cited by 26 publications

References 22 publications

HIV vaccine delayed boosting increases Env variable region 2–specific antibody effector functions

HIV vaccine delayed boosting increases Env variable region 2–specific antibody effector functions

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

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Blocking α 4 β 7 integrin binding to SIV does not improve virologic control

Cited by 26 publications

References 22 publications

HIV vaccine delayed boosting increases Env variable region 2–specific antibody effector functions

HIV vaccine delayed boosting increases Env variable region 2–specific antibody effector functions

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

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Blocking α ₄ β ₇ integrin binding to SIV does not improve virologic control