The Anti-Hiv Candidate Abx464 Dampens Intestinal Inflammation by Triggering Il-22 Production in Activated Macrophages

Abstract

The progression of human immunodeficiency virus (HIV) is associated with mucosal damage in the gastrointestinal (GI) tract. This damage enables bacterial translocation from the gut and leads to subsequent inflammation. Dextran sulfate sodium (DSS-exposure) is an established animal model for experimental colitis that was recently shown to recapitulate the link between GI-tract damage and pathogenic features of SIV infection. The current study tested the protective properties of ABX464, a first-in-class anti-HIV drug candidate currently in phase II clinical trials. ABX464 treatment strongly attenuated DSS-induced colitis in mice and produced a long-term protection against prolonged DSS-exposure after drug cessation. Consistently, ABX464 reduced the colonic production of the inflammatory cytokines IL-6 and TNFα as well as that of the chemoattractant MCP-1. However, RNA profiling analysis revealed the capacity of ABX464 to induce the expression of IL-22, a cytokine involved in colitis tissue repair, both in DSS-treated mice and in LPS-stimulated bone marrow-derived macrophages. Importantly, anti-IL-22 antibodies significantly reduced the protective effect of ABX464 on colitis in DSS-treated mice. Because reduced IL-22 production in the gut mucosa is an established factor of HIV and DSS-induced immunopathogenesis, our data suggest that the anti-inflammatory properties of ABX464 warrant exploration in both HIV and inflammatory ulcerative colitis (UC) disease.

A Double Edged Sword Role of Interleukin-22 in Wound Healing and Tissue Regeneration

“…Similarly, impairment in IL-22 production due to Th22 depletion in mucosal gut is a significant factor in HIV mediated mucosal immunopathogenesis (73). Anti-HIV candidate Abx464 reduces intestinal inflammation by stimulating activated macrophages to produce more IL-22 in mice model (109). Inoculation of IL-22 along with IL-18 to murine model reiterated the capability of flagellin to inhibit or eradicate Rotavirus (RV) infection (110).…”

Both anti-inflammatory and antiviral properties of novel drug candidate ABX464 are mediated by modulation of RNA splicing

“…Thus, the anti-inflammatory activity of ABX464 is potentially relevant for the intended use in treating HIV patients, in whom the inflammation around viral reservoirs was shown to substantially contribute to adverse cardiovascular and tumorigenic effects despite long-term ART-treatment. In addition, ABX464 protects mice from the lethal effects of DSS (Dextran Sulphate Sodium), which is a key animal model for inflammatory bowel disease 1 . Patients with UC may benefit from ABX464 which has demonstrated safety in phase 2 clinical trial (ABIVAX, data in file) and has a mode of action different from classical medications including corticosteroids, immunomodulators and biologic treatments.…”

Clinical importance of IL-22 cascade in IBD

“…Importantly, indigo naturalis is one of the ligands of Ahr, and a recent study in mice demonstrates that the therapeutic effect of indigo naturalis is mediated by Ahr-dependent activation of IL-22 pathway [ 106 ]. In addition, the therapeutic potential of other Ahr ligands such as Ficz [ 65 ] and ABX464 (the first-in-class anti-HIV drug candidate) [ 107 ] against experimental colitis has been reported. These findings clearly highlight the activation of IL-22 as a promising therapeutic measure for IBD, particularly UC.…”