Ryan Emily S, Micci Luca, Fromentin Rémi, Paganini Sara, McGary Colleen S, Easley Kirk, Chomont Nicolas, Paiardini Mirko
Division of Microbiology & Immunology, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Department of Microbiology, Infectiology and Immunology, Université de Montréal, Faculty of Medicine, and Centre de Recherche du CHUM, Montreal, Québec, Canada.
PLoS Pathog. 2016 Feb 1;12(2):e1005412. doi: 10.1371/journal.ppat.1005412. eCollection 2016 Feb.
In HIV/SIV-infected humans and rhesus macaques (RMs), a severe depletion of intestinal CD4(+) T-cells producing interleukin IL-17 and IL-22 associates with loss of mucosal integrity and chronic immune activation. However, little is known about the function of IL-17 and IL-22 producing cells during lentiviral infections. Here, we longitudinally determined the levels and functions of IL-17, IL-22 and IL-17/IL-22 producing CD4(+) T-cells in blood, lymph node and colorectum of SIV-infected RMs, as well as how they recover during effective ART and are affected by ART interruption. Intestinal IL-17 and IL-22 producing CD4(+) T-cells are polyfunctional in SIV-uninfected RMs, with the large majority of cells producing four or five cytokines. SIV infection induced a severe dysfunction of colorectal IL-17, IL-22 and IL-17/IL-22 producing CD4(+) T-cells, the extent of which associated with the levels of immune activation (HLA-DR(+)CD38(+)), proliferation (Ki-67+) and CD4(+) T-cell counts before and during ART. Additionally, Th17 cell function during ART negatively correlated with residual plasma viremia and levels of sCD163, a soluble marker of inflammation and disease progression. Furthermore, IL-17 and IL-22 producing cell frequency and function at various pre, on, and off-ART experimental points associated with and predicted total SIV-DNA content in the colorectum and blood. While ART restored Th22 cell function to levels similar to pre-infection, it did not fully restore Th17 cell function, and all cell types were rapidly and severely affected--both quantitatively and qualitatively--after ART interruption. In conclusion, intestinal IL-17 producing cell function is severely impaired by SIV infection, not fully normalized despite effective ART, and strongly associates with inflammation as well as SIV persistence off and on ART. As such, strategies able to preserve and/or regenerate the functions of these CD4(+) T-cells central for mucosal immunity are critically needed in future HIV cure research.
在感染HIV/SIV的人类和恒河猴（RM）中，肠道内产生白细胞介素IL-17和IL-22的CD4(+) T细胞严重耗竭，这与黏膜完整性丧失和慢性免疫激活有关。然而，关于慢病毒感染期间产生IL-17和IL-22的细胞的功能，我们知之甚少。在此，我们纵向测定了感染SIV的恒河猴血液、淋巴结和结肠直肠中产生IL-17、IL-22和IL-17/IL-22的CD4(+) T细胞的水平和功能，以及它们在有效抗逆转录病毒治疗（ART）期间如何恢复以及受ART中断的影响。在未感染SIV的恒河猴中，肠道内产生IL-17和IL-22的CD4(+) T细胞具有多种功能，绝大多数细胞能产生四种或五种细胞因子。SIV感染导致结肠直肠中产生IL-17、IL-22和IL-17/IL-22的CD4(+) T细胞严重功能障碍，其程度与免疫激活水平（HLA-DR(+)CD38(+)）、增殖（Ki-67+）以及ART治疗前后的CD4(+) T细胞计数相关。此外，ART期间Th17细胞功能与残余血浆病毒血症以及sCD163水平呈负相关，sCD163是炎症和疾病进展的可溶性标志物。此外，在ART治疗前、治疗期间和治疗后的各个实验点，产生IL-17和IL-22的细胞频率及功能与结肠直肠和血液中的总SIV-DNA含量相关且可预测其含量。虽然ART可将Th22细胞功能恢复到与感染前相似的水平，但并未完全恢复Th17细胞功能，并且在ART中断后，所有细胞类型在数量和质量上均迅速受到严重影响。总之，肠道内产生IL-17的细胞功能因SIV感染而严重受损，尽管进行了有效的ART治疗也未完全恢复正常，并且与炎症以及ART治疗期间和中断后的SIV持续存在密切相关。因此，在未来的HIV治愈研究中，迫切需要能够保存和/或恢复这些对黏膜免疫至关重要的CD4(+) T细胞功能的策略。
