Early treatment with anti-α4β7 antibody facilitates increased gut macrophage maturity in SIV-infected rhesus macaques

Abstract

Despite advances in combination antiretroviral therapy (cART), people living with HIV (PLWH) continue to experience gastrointestinal dysfunction. Infusions of anti-α₄β₇ monoclonal antibodies (mAbs) have been proposed to increase virologic control during simian immunodeficiency virus (SIV) infection in macaques with mixed results. Recent evidences suggested that therapeutic efficacy of vedolizumab (a humanized anti-α₄β₇ mAb), during inflammatory bowel diseases depends on microbiome composition, myeloid cell differentiation, and macrophage phenotype. We tested this hypothesis in SIV-infected, anti-α₄β₇ mAb-treated macaques and provide flow cytometric and microscopic evidence that anti-α₄β₇ administered to SIV-infected macaques increases the maturity of macrophage phenotypes typically lost in the small intestines during SIV disease progression. Further, this increase in mature macrophage phenotype was associated with tissue viral loads. These phenotypes were also associated with dysbiosis markers in the gut previously identified as predictors of HIV replication and immune activation in PLWH. These findings provide a novel model of anti-α₄β₇ efficacy offering new avenues for targeting pathogenic mucosal immune response during HIV/SIV infection.

Keywords: butyrate; macrophage maturation; microbiome; mucosal immunology; myeloid cells; simian immunodeficiency virus (SIV); viral reservoir; α4β7 integrin.