IL-21 and probiotic therapy improve Th17 frequencies, microbial translocation, and microbiome in ARV-treated, SIV-infected macaques

Abstract

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 TH17 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 TH17 cells, had limited recovery. Here, we sought to promote TH17 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 TH17 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.

Microbial translocation and microbiome dysbiosis in HIV-associated immune activation

“…In addition, the authors observed improved functionality of antigen presenting cells (APCs) without overt DC activation, suggesting that innate immunity can also be enhanced by probiotic supplementation [70]. In a follow up study, ART-treated SIV-infected macaques were given a combination of probiotics and IL-21, which also improved frequencies of Th17 cells, potentially due to an observed decrease in Kyn:Trp ratios and decreased IDO activity in plasma [105**]. …”

Effects of Fecal Microbial Transplantation on Microbiome and Immunity in Simian Immunodeficiency Virus-Infected Macaques

“…Th17 and Th22 cells, important components of mucosal immunity, are significantly depleted in HIV and SIV infection, and this depletion is associated with reduced barrier integrity, microbial translocation, and systemic immune activation (32)(33)(34). Previous studies have demonstrated a connection between commensal bacteria and the ability of probiotic therapy to enhance intestinal Th17 frequencies (15,35,36). Thus, we hypothesized that alteration of the microbiome through FMT might restore Th17 and Th22 frequencies.…”

“…ϩ T cell restoration in the GI tract after probiotic therapy or therapy with probiotics supplemented with interleukin-21 (IL-21) (15,16). In HIV-infected individuals, probiotics have been shown to decrease inflammation and microbial translocation (17,18).…”

A pilot study on the effects of probiotic supplementation on neuropsychological performance and microRNA‐29a‐c levels in antiretroviral‐treated HIV‐1‐infected patients

“…Few studies have been published on the role of a probiotic supplementation on SIV+ monkeys and on HIV+ humans, with promising results regarding the immune reconstitution of the gut barrier and immune response (Cunningham-Rundles et al, 2011;d'Ettorre, Ceccarelli, Andreotti, et al, 2015;d'Ettorre, Ceccarelli, Giustini, et al, 2015;Ortiz et al, 2016;Villar-García et al, 1999). No information is available on the effects of a probiotic supplementation on brain function and behavior of HIV+ subjects.…”