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 Fréd́eric; Horowitz, Amir; Lim, Jean K.; Chomont, Nicolas; Rahman, Adeeb; Montaner, Luis J.; Ndhlovu, Lishomwa C.; Mehandru, Saurabh

doi:10.1126/scitranslmed.aau4711

Cited by 61 publications

(47 citation statements)

References 66 publications

(90 reference statements)

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“…Moreover, immune aggregates may be retained efficiently in the mucus by binding of the Fc domain of IgG to mucins and specific binding in the vaginal tract to MUC16 (164). Analogous mechanisms may act on other mucosal surfaces, such as those in the gastrointestinal tract (165).…”

Section: Antibody Capture Of Infectious Hiv Particles/aggregationmentioning

confidence: 99%

Update on Fc-Mediated Antibody Functions Against HIV-1 Beyond Neutralization

Dispinseri

Iannone

et al. 2019

Front. Immunol.

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Antibodies (Abs) are the major component of the humoral immune response and a key player in vaccination. The precise Ab-mediated inhibitory mechanisms leading to in vivo protection against HIV have not been elucidated. In addition to the desired viral capture and neutralizing Ab functions, complex Ab-dependent mechanisms that involve engaging immune effector cells to clear infected host cells, immune complexes, and opsonized virus have been proposed as being relevant. These inhibitory mechanisms involve Fc-mediated effector functions leading to Ab-dependent cellular cytotoxicity, phagocytosis, cell-mediated virus inhibition, aggregation, and complement inhibition. Indeed, the decreased risk of infection observed in the RV144 HIV-1 vaccine trial was correlated with the production of non-neutralizing inhibitory Abs, highlighting the role of Ab inhibitory functions besides neutralization. Moreover, Ab isotypes and subclasses recognizing specific HIV envelope epitopes as well as pecular Fc-receptor polymorphisms have been associated with disease progression. These findings further support the need to define which Fc-mediated Ab inhibitory functions leading to protection are critical for HIV vaccine design. Herein, based on our previous review Su & Moog Front Immunol 2014, we update the different inhibitory properties of HIV-specific Abs that may potentially contribute to HIV protection.

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Section: Antibody Capture Of Infectious Hiv Particles/aggregationmentioning

confidence: 99%

Update on Fc-Mediated Antibody Functions Against HIV-1 Beyond Neutralization

Dispinseri

Iannone

et al. 2019

Front. Immunol.

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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: 90%

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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“…Why we observe a significant enrichment of naïve B cells in vedolizumab endoscopic remitters cannot be fully answered based on our findings, and raises the question whether a vedolizumab induced depletion of this cell population is key to its therapeutic success. Indeed, recent data on a small cohort of HIVinfected IBD patients demonstrated that vedolizumab therapy importantly reduced naïve B cells in intestinal mucosa, 29 preventing subsequent priming by dendritic cells, who are surveying the mucosal barrier for invading pathogens.…”

Section: Discussionmentioning

confidence: 99%

Expression Levels of 4 Genes in Colon Tissue Might Be Used to Predict Which Patients Will Enter Endoscopic Remission After Vedolizumab Therapy for Inflammatory Bowel Diseases

Verstockt

Veny

et al. 2020

Clinical Gastroenterology and Hepatology

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BACKGROUND & AIMS: We aimed to identify biomarkers that might be used to predict responses of patients with inflammatory bowel diseases (IBD) to vedolizumab therapy. METHODS: We obtained biopsies from inflamed colon of patients with IBD who began treatment with vedolizumab (n [ 31) or tumor necrosis factor (TNF) antagonists (n [ 20) and performed RNA-sequencing analyses. We compared gene expression patterns between patients who did and did not enter endoscopic remission (absence of ulcerations at month 6 for patients with Crohn's disease or Mayo endoscopic subscore £1 at week 14 for patients with ulcerative colitis) and performed pathway analysis and cell deconvolution for training (n [ 20) and validation (n [ 11) datasets. Colon biopsies were also analyzed by immunohistochemistry. We validated a baseline gene expression pattern associated with endoscopic remission after vedolizumab therapy using 3 independent datasets (n [ 66). RESULTS: We identified significant differences in expression levels of 44 genes between patients who entered remission after vedolizumab and those who did not; we found significant increases in leukocyte migration in colon tissues from patients who did not enter remission (P < .006). Deconvolution methods identified a significant enrichment of monocytes (P [ .005), M1macrophages (P [ .05), and CD4D T cells (P [ .008) in colon tissues from patients who did not enter remission, whereas colon tissues from patients in remission had higher numbers of naïve B cells before treatment (P [ .05). Baseline expression levels of PIWIL1, MAATS1, RGS13, and DCHS2 identified patients who did vs did not enter remission with 80% accuracy in the training set and 100% accuracy in validation dataset 1. We validated these findings in the 3 independent datasets by microarray, RNA sequencing and quantitative PCR analysis (P [ .003). Expression levels of these 4 genes did not associate with response to anti-TNF agents. We confirmed the presence of proteins encoded by mRNAs using immunohistochemistry. CONCLUSIONS: We identified 4 genes whose baseline expression levels in colon tissues of patients with IBD associate with endoscopic remission after vedolizumab, but not anti-TNF, treatment. We validated this signature in 4 independent datasets and also at the protein level. Studies of these genes might provide insights into the mechanisms of action of vedolizumab.

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

Cited by 61 publications

References 66 publications

Update on Fc-Mediated Antibody Functions Against HIV-1 Beyond Neutralization

Update on Fc-Mediated Antibody Functions Against HIV-1 Beyond Neutralization

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

Expression Levels of 4 Genes in Colon Tissue Might Be Used to Predict Which Patients Will Enter Endoscopic Remission After Vedolizumab Therapy for Inflammatory Bowel Diseases

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