Ortiz A M, Klase Z A, DiNapoli S R, Vujkovic-Cvijin I, Carmack K, Perkins M R, Calantone N, Vinton C L, Riddick N E, Gallagher J, Klatt N R, McCune J M, Estes J D, Paiardini M, Brenchley J M
Program in Tissue Immunity and Repair and Immunopathogenesis Section, Lab of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA.
Department of Biological Sciences, University of the Sciences, Philadelphia, Pennsylvania, USA.
Mucosal Immunol. 2016 Mar;9(2):458-67. doi: 10.1038/mi.2015.75. Epub 2015 Aug 19.
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 interleukin (IL)-21 to a limited number of ARV-treated, probiotic-supplemented, Simian Immunodeficiency Virus (SIV)-infected pigtailed macaques. We demonstrate that probiotic and IL-21 supplementation of ARVs are associated with enhanced polyfunctional Th17 expansion and reduced markers of microbial translocation and dysbiosis as compared with infected controls receiving ARVs alone. Importantly, treatment resulted in fewer morbidities compared with 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.
接受抗逆转录病毒（ARV）治疗的HIV感染者死亡率增加，这部分归因于持续的免疫功能障碍，部分原因是胃肠道屏障异常。特别是，胃肠道Th17细胞重建不良与功能失调的免疫刺激性微生物群通过受损的肠道上皮屏障发生残余易位相关。我们之前已经证明，在HIV感染的非人灵长类动物模型中，口服益生菌可促进ARV治疗期间肠道CD4(+) T细胞的重建增加；然而，重要的黏膜T细胞亚群，如Th17细胞，恢复有限。在此，我们试图通过向有限数量的接受ARV治疗、补充益生菌的感染猿猴免疫缺陷病毒（SIV）的猪尾猕猴施用白细胞介素（IL）-21来促进Th17细胞的恢复。我们证明，与仅接受ARV的感染对照相比，ARV补充益生菌和IL-21与多功能Th17细胞的增强扩增以及微生物易位和生态失调标志物的减少相关。重要的是，与对照相比，治疗导致的发病率更低，并且与免疫激活增加或病毒抑制丧失无关。我们提出，将ARV与旨在恢复肠道内环境稳定的治疗方法相结合，可能会显著改善接受ARV治疗的HIV感染者的疾病预后。
