Abstract
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.
Highlights
Human immunodeficiency virus (HIV) infection induces high and persistent levels of immune activation and inflammation, which are associated with the loss of CD4+ T cells and accelerated disease progression [1, 2]
Flow cytometric analysis was performed on peripheral blood mononuclear cells (PBMCs) and RBderived cells according to standard procedures using a panel of monoclonal antibody (mAb) that others and we have shown to be cross-reactive with rhesus macaques (RMs) immune cells [10, 19] (Supplementary Table 2)
To determine the safety and tolerability of the combined IL21 and anti-α4β7 mAb administration in non-human primates, four healthy, simian immunodeficiency virus (SIV)-uninfected RMs were treated with two doses of anti-α4β7 mAb (50 mg/kg, intravenous) at a 3week interval and seven weekly doses of recombinant rhesus IL-21–IgFc (IL-21-Fc, 100 μg/kg, subcutaneous)
Summary
Human immunodeficiency virus (HIV) infection induces high and persistent levels of immune activation and inflammation, which are associated with the loss of CD4+ T cells and accelerated disease progression [1, 2]. ART-treated HIV-infected individuals can still present persistent chronic inflammation, limited CD4+ T-cell reconstitution, and mucosal immune dysfunction [1, 4,5,6], which have all been linked to increased. We showed that in simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) loss of IL-21– producing CD4+ T cells in the gut is associated with TH17 cell depletion, loss of gut mucosa integrity, and mucosal immune dysfunction [8]. We have shown that administration of a rhesus IL-21–IgFc fusion protein in acute [9] or chronic ART-treated SIV-infected RMs [10] resulted in the preservation of intestinal TH17 cells, improved mucosal immune function, and reduced microbial translocation. It has been shown that IL-21 promotes degranulation and effector functions of CD8+ T cells [12, 13] and that IL-21–producing HIV-1–specific CD8+ T cells are more abundant in elite controllers [14]
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