Targeting α4β7 integrin reduces mucosal transmission of simian immunodeficiency virus and protects gut-associated lymphoid tissue from infection

Abstract

α4β7 integrin-expressing CD4(+) T cells preferentially traffic to gut-associated lymphoid tissue (GALT) and have a key role in HIV and simian immunodeficiency virus (SIV) pathogenesis. We show here that the administration of an anti-α4β7 monoclonal antibody just prior to and during acute infection protects rhesus macaques from transmission following repeated low-dose intravaginal challenges with SIVmac251. In treated animals that became infected, the GALT was significantly protected from infection and CD4(+) T cell numbers were maintained in both the blood and the GALT. Thus, targeting α4β7 reduces mucosal transmission of SIV in macaques.

Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare no competing financial interests. The findings in this report are those of the authors and do not necessarily reflect the views of the Centers for Disease Control and Prevention.

Figures

Fig. 1. Kinetics of plasma viral load and tissue and organ specific pro-viral DNA loads

Plasma viral loads from two groups of macaques (n=12 for each group) that received 50 mg/kg of either aα4β7-mAb (a) or a rhesus IgG (b) I.V. at 3 week intervals following the initiation of six, once-weekly, low-dose intra-vaginal challenges with SIVmac251 (arrows). Kaplan-Meier curves based on plasma viral RNA (n=12 each group; log-rank test; p=0.002) (c).Pro-viral DNA load (# of copies/ng DNA) in rectal biopsies from α4β7-mAb (d) or IgG control macaques (e) (n=6 for α4β7-mAb, n=10 for IgG control).Median values of data in d and e (random mixed effects (RME) model; p=0.006) (f). Two infected macaques from each group (α4β7-mAb in blue (T), control IgG in red (C)) were sacrificed at 2 weeks p.i. (filled circles) and two sacrificed at 16–18 weeks p.i. (open circles). Pro-viral DNA load (# copies/ng DNA) in jejunal, ileum and colon tissue samples from both groups (n=4; Mann-Whitney U-test; P<0.01) (g), spleen, and internal iliac, colonic, inguinal, axillary, mesenteric lymph-nodes (n=4; Mann-Whitney U-test; P<0.01) from both groups (h). Pro-viral DNA load (# copies/ng DNA) from cervical tissue samples from 3 macaques from both groups (i). Macaque I.D.’s in panels a, b, d and e are specified.

Fig. 2. Frequency of lymphocyte subsets from infected macaque PBMCs and inhibition of MAdCAM or SIVmac251 gp120 by α4β7-mAb

Changes in the absolute numbers of CD4+ T cells (top left), CD8+ T cells (top right), NK cells (bottom left) and B cells (bottom right) in PBMC from infected α4β7-mAb (blue) or IgG treated (red) and uninfected (purple) macaques (n=6 for α4β7-mAb infected, n=10 for IgG infected, n=8 for uninfected); median values are given (RME model) (a).Frequencies of CD4+CD45+ T cells in cytobrush samples (n=6 for α4β7-mAb, n=9 for IgG; RME model; p=0.052) (b), and gut biopsy(c) (n=6 for α4β7 mAb and n=9 for IgG; RME model; p<0.0001).Flow-cytometric analysis of CD4+α4β7+ T cells stained with PE labeled MAdCAM-Ig in the presence of IgG (d) or α4β7-mAb (e) in the presence of MgCl2. MAdCAM-Ig-reactive cells are included within the blue box and the percent reactive cells are indicated. Binding of neutravidin-PE alone (lane 1), increasing amounts of PE labeled SIVMac251 gp120 (lanes 2–4), 2μg PE labeled SIVMac251 gp120 in the presence of an unlabeled α4 mAb (lane 5), and 2μg PE labeled SIVMac251 gp120 in the absence of divalent cations (lane 6) as controls, to CD4+α4β7+ T cells (f). Flow-cytometric profile of CD4+α4β7+ T cells stained with neutravidin PE alone (grey) or PE labeled SIVmac251 gp120 in the absence (blue) or presence (red) of unlabeled α4β7-mAb (g). CD4+α4β7+ T cells stained with neutravidin-PE alone (grey) or labeled SIVmac251 gp120 in the absence (blue) or presence (red) of unlabeled MAdCAM-Ig (h). Experiments shown in panels f, g and h were performed in presence of an anti-CD4 mAb.