IL-21 and Probiotic Therapy Improve T(H)17 Frequencies, Microbial Translocation, and Microbiome in ARV-Treated, SIV-Infected Macaques

Increased mortality in antiretroviral (ARV)-treated, HIV-infected individuals has been attributed to persistent immune dysfunction, in part due to abnormalities at the gastrointestinal barrier. In particular, the poor reconstitution of gastrointestinal T(H)17 cells correlates with residual translocation of dysbiotic, immunostimulatory microflora across a compromised intestinal epithelial barrier. We have previously demonstrated that oral probiotics promote increased intestinal CD4+ T-cell reconstitution during ARV treatment in a non-human primate model of HIV infection; however, essential mucosal T-cell subsets, such as T(H)17 cells, had limited recovery. Here, we sought to promote T(H)17 cell recovery by administering IL-21 to a limited number of ARV-treated, probiotic-supplemented, SIV-infected pigtailed macaques. We demonstrate that probiotic and IL-21 supplementation of ARVs is associated with enhanced polyfunctional T(H)17 expansion and reduced markers of microbial translocation and dysbiosis as compared to infected controls receiving ARVs alone. Importantly, treatment resulted in fewer morbidities compared to controls, and was independent of increased immune activation or loss of viral suppression. We propose that combining ARVs with therapeutics aimed at restoring intestinal stasis may significantly improve disease prognosis of ARV-treated, HIV-infected, individuals.