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.

Dual role for microbial short-chain fatty acids in modifying SIV disease trajectory following anti-α4β7 antibody administration

“…This study was planned, conducted, and reported here following the Animal Research: Reporting In Vivo Experiments (ARRIVE) guidelines. Ethical approval was obtained from the UNMC Institutional Animal Care and Use Committee (IACUC) and Institutional Biosafety Committee (IBC) for “Gut Trafficking Cells in SIV Infection” (Protocol #15-102-12) prior to initiation of the study as reported previously [ 25 ].…”

“…Eight mAb infusions were administered regularly until week 23 (every three weeks). The protocol is shown in Figure 1(a) and was reported previously [ 25 ].…”

“…RNA was isolated by spin column chromatography using a QIAamp Viral RNA Mini Kit (Qiagen, Germantown, MD, USA; Product #52906). As previously described, viral loads (VLs) were determined by real-time PCR using TaqMan® RNA-to-Ct™ 1-Step Kit (Thermo Fisher Scientific Baltics UAB, Vilnius, Lithuania, Product #4392938), and standard curves were evaluated in parallel [ 25 , 33 , 34 ]. Real-time PCR was performed for 40 cycles with a 1-min annealing/extension step at 60 °C.…”

“…We recently proposed that the mechanism by which anti-α4β7 induces its therapeutic effect may be due to its ability to facilitate increased lamina propria macrophage maturity, which is typically lost during SIV pathogenesis. This relative increase in immature gut macrophages compared to mature gut macrophages that occurs during HIV/SIV infection may contribute to the chronic pro-inflammatory immune response [ 25 , 26 ].…”

Targeting HIV persistence in the tissue

“…However, a clinical trial investigating anti-α4β7 monoclonal antibody therapy in PWH did not show positive effects on viral rebound upon ART interruption [58]. Moreover, in SIV-infected macaques, this therapy increased expression of CD206 and CD163 on mature duodenal macrophages, which correlated with higher viral loads [59].…”