Anti-α4β7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1 infected individuals

Uzzan, Mathieu; Tokuyama, Minami; Rosenstein, Adam; Tomescu, Costin; SahBandar, Ivo N.; Ko, Huaibin M.; Leyre, Louise; Chokola, Anupa; Kaplan-Lewis, Emma; Rodrı́guez, Gabriela; Seki, Akihiro; Corley, Michael J.; Aberg, Judith A.; Porte, Annalena La; Park, Eun‐Young; Ueno, Hideki; Oikonomou, Ioannis; Doron, Itai; Iliev, Iliyan D.; Chen, Benjamin; Lui, Jennifer; Schacker, Timothy W.; Furtado, Gláucia C.; Lira, Sérgio A.; Colombel, Jean–Frédéric; Horowitz, Amir; Lim, Jean K.; Chomont, Nicolas; Montaner, Luis J.; Ndhlovu, Lishomwa C.; Mehandru, Saurabh

doi:10.1101/346684

Cited by 7 publications

(10 citation statements)

References 60 publications

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“…Our results, in agreement with others, 44 also rule out a role for α4β7 on plasma cell recruitment to the intestinal mucosa. Indeed, while both vedolizumab and anti-TNF significantly reduced the overall plasma cell population in the colonic mucosa of UC patients, the remaining plasma cells showed high percentages of α4β7 expression.…”

Section: Discussionsupporting

confidence: 94%

“…Nonetheless, previous evidence supports the role of α4β7-mediated interactions in maintaining those lymphoid aggregates abundant in the ileal mucosa. 44 Uzzan and colleagues studied the ileum and left colon [both uninvolved mucosa] of UC patients with concomitant chronic HIV infection. In this unique cohort they showed that vedolizumab, even in the absence of inflammation, decreased the number of naïve T cells and B cells in lymphoid aggregates.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, while both vedolizumab and anti-TNF significantly reduced the overall plasma cell population in the colonic mucosa of UC patients, the remaining plasma cells showed high percentages of α4β7 expression. 44 This observation suggests that, in contrast to other lymphocytes, plasma cells may not use α4β7 as a receptor for intestinal homing. Beyond binding to endothelial adhesion molecules [MAdCAM-1 and VCAM-1], α4β7 has been described to use the extracellular matrix protein fibronectin as ligand.…”

Section: Discussionmentioning

confidence: 99%

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Dissecting Common and Unique Effects of Anti-α4β7 and Anti-Tumor Necrosis Factor Treatment in Ulcerative Colitis

Veny

Garrido-Trigo

Corraliza

et al. 2020

Journal of Crohn's and Colitis

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Background and Aims Vedolizumab is an anti-α4β7 antibody approved for the treatment of ulcerative colitis (UC). Although it is assumed that vedolizumab blocks intestinal homing of lymphocytes, its effects on different intestinal cell populations are not fully stablished. In order to establish the unique mechanisms of action of vedolizumab in UC patients, we compared its effects to those induced by anti-tumor necrosis factor (TNF). Methods Patients with active UC (endoscopic Mayo score >1) starting vedolizumab (n=33) or anti-TNF (n=45) and controls (n=22) were included. Colon biopsies (at weeks 0, 14 and 46) and blood samples (at weeks 0, 2, 6,14, 30 and 46) were used for cell phenotyping, transcriptional analysis (qPCR), and to measure receptor occupancy. Results Vedolizumab, in contrast to anti-TNF, significantly reduced the proportion of α4β7 + cells within intestinal T subsets while preserving the percentage of α4β7 + plasma cells. The marked decrease in α4β7 did not change the percentage of colonic αEβ7 + cells (at 46 weeks). Both vedolizumab and anti-TNF significantly downregulated inflammation-related genes in the colon of responders (Mayo score <2). Moreover, both treatments significantly decreased the percentage of intestinal, but not blood, total lymphocytes (T and plasma cells), as well as the proportion of α4β1 + cells within intestinal T lymphocytes. Conclusions Our data shows that while vedolizumab and anti-TNF block two unrelated targets, they induce remarkably similar effects. On the other hand, vedolizumab’s unique mechanism of action relies on blocking intestinal trafficking of α4β7 T cells, despite effectively binding to B and plasma cells that express α4β7.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Dissecting Common and Unique Effects of Anti-α4β7 and Anti-Tumor Necrosis Factor Treatment in Ulcerative Colitis

Veny

Garrido-Trigo

Corraliza

et al. 2020

Journal of Crohn's and Colitis

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“…In another recent study, 6 HIV‐infected individuals who also had mild inflammatory bowel disease received vedolizumab concomitant with suppressive ART 42 . Although continued ART treatment made it impossible to detect significant virologic effects, anti‐α4β7 therapy led to a significant and unexpected attenuation of lymphoid aggregates in the gut compartment, most notably in the terminal ileum, along with a reduction in naïve T cells and a decrease in CD4 + T‐cell activation.…”

Section: Clinical Results With Anti‐α4β7 Antibodies In Hiv Infectionmentioning

confidence: 99%

Integrin α4β7 in HIV-1 infection: A critical review

Liu

Lusso

2020

Journal of Leukocyte Biology

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Over the past decade, a series of observations linking 4 7, the principal gut-homing integrin, with various aspects of HIV-1 infection have generated considerable interest in the field of HIV-1 research. After the initial report that the major HIV-1 envelope glycoprotein, gp120, can bind to 4 7, intensive research efforts have been focused on the role of 4 7 as a key factor in HIV-1 pathogenesis and as a potential target for prevention and treatment. The interaction between 4 7 and its natural ligand, MAdCAM-1, directs infected CD4 + T cells and HIV-1 virions carrying incorporated 4 7 to the gut mucosa, which may facilitate HIV-1 seeding and replication in the intestinal compartment during the early stages of infection. In addition, cells that express high levels of 4 7, such as Th17 cells, represent preferential targets for infection, and their frequency in the circulation was shown to correlate with susceptibility to HIV-1 infection and disease progression. A number of in vivo studies in nonhuman primates have investigated whether blockage of 4 7 may affect SIV transmission and pathogenesis. Administration of a primatized anti-4 7 antibody that blocks MAdCAM-1 binding to 4 7 was reported to reduce SIV mucosal transmission in rhesus macaques. However, the mechanism responsible for such a protective effect is still undefined, and conflicting results have been reported on the effects of the same antibody, in combination with ART, during the early chronic phase of SIV infection. Thus, despite a series of tantalizing results accrued over the past decade, the jury is still out on the role of 4 7 in HIV-1 infection.

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“…The direct link between α4β7 expression and the viral reservoir is supported by recent findings by Uzzan et al It was recently showed that administering the Food and Drug Administration (FDA)-approved drug Vedolizumab that masks α4β7 expression in leukocytes reduces the size of lymphoid aggregates in the terminal ileum of HIV infected individuals [ 61 ]. Lymphoid aggregates have been suggested as key foci in which the latent reservoir is maintained within the gut.…”

Section: Discussionmentioning

confidence: 97%

Retinoic Acid Improves the Recovery of Replication-Competent Virus from Latent SIV Infected Cells

Olwenyi

Acharya

Routhu

et al. 2020

Cells

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The accurate estimation and eradication of Human Immunodeficiency Virus (HIV) viral reservoirs is limited by the incomplete reactivation of cells harboring the latent replication-competent virus. We investigated whether the in vitro and in vivo addition of retinoic acid (RA) enhances virus replication and improves the detection of latent virus. Peripheral blood mononuclear cells (PBMCs) from naive and anti-retroviral therapy (ART)-treated SIV-infected rhesus macaques (RMs) were cultured in vitro with anti-CD3/CD28 + IL-2 in the presence/absence of RA. Viral RNA and p27 levels were quantified using RT-qPCR and ELISA, respectively. Viral reservoirs were estimated using the Tat/Rev-Induced Limited Dilution Assay (TILDA) and Quantitative Viral Outgrowth Assay (QVOA). In vitro and in vivo measures revealed that there was also an increase in viral replication in RA-treated versus without RA conditions. In parallel, the addition of RA to either CD3/CD28 or phorbol myristate acetate (PMA)/ionomycin during QVOA and TILDA, respectively, was shown to augment reactivation of the replication-competent viral reservoir in anti-retroviral therapy (ART)-suppressed RMs as shown by a greater than 2.3-fold increase for QVOA and 1 to 2-fold increments for multi-spliced RNA per million CD4+ T cells. The use of RA can be a useful approach to enhance the efficiency of current protocols used for in vitro and potentially in vivo estimates of CD4+ T cell latent reservoirs. In addition, flow cytometry analysis revealed that RA improved estimates of various viral reservoir assays by eliciting broad CD4 T-cell activation as demonstrated by elevated CD25 and CD38 but reduced CD69 and PD-1 expressing cells.

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Anti-α4β7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1 infected individuals

Cited by 7 publications

References 60 publications

Dissecting Common and Unique Effects of Anti-α4β7 and Anti-Tumor Necrosis Factor Treatment in Ulcerative Colitis

Dissecting Common and Unique Effects of Anti-α4β7 and Anti-Tumor Necrosis Factor Treatment in Ulcerative Colitis

Integrin α4β7 in HIV-1 infection: A critical review

Retinoic Acid Improves the Recovery of Replication-Competent Virus from Latent SIV Infected Cells

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