Sereti Irini, Estes Jacob D, Thompson William L, Morcock David R, Fischl Margaret A, Croughs Thérèse, Beq Stéphanie, Lafaye de Micheaux Sylvie, Yao Michael D, Ober Alexander, Wilson Eleanor M P, Natarajan Ven, Imamichi Hiromi, Boulassel Mohamed R, Lederman Michael M, Routy Jean-Pierre
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, Maryland, United States of America.
PLoS Pathog. 2014 Jan 30;10(1):e1003890. doi: 10.1371/journal.ppat.1003890. eCollection 2014 Jan.
Despite antiretroviral therapy (ART), some HIV-infected persons maintain lower than normal CD4(+) T-cell counts in peripheral blood and in the gut mucosa. This incomplete immune restoration is associated with higher levels of immune activation manifested by high systemic levels of biomarkers, including sCD14 and D-dimer, that are independent predictors of morbidity and mortality in HIV infection. In this 12-week, single-arm, open-label study, we tested the efficacy of IL-7 adjunctive therapy on T-cell reconstitution in peripheral blood and gut mucosa in 23 ART suppressed HIV-infected patients with incomplete CD4(+) T-cell recovery, using one cycle (consisting of three subcutaneous injections) of recombinant human IL-7 (r-hIL-7) at 20 µg/kg. IL-7 administration led to increases of both CD4(+) and CD8(+) T-cells in peripheral blood, and importantly an expansion of T-cells expressing the gut homing integrin α4β7. Participants who underwent rectosigmoid biopsies at study baseline and after treatment had T-cell increases in the gut mucosa measured by both flow cytometry and immunohistochemistry. IL-7 therapy also resulted in apparent improvement in gut barrier integrity as measured by decreased neutrophil infiltration in the rectosigmoid lamina propria 12 weeks after IL-7 administration. This was also accompanied by decreased TNF and increased FOXP3 expression in the lamina propria. Plasma levels of sCD14 and D-dimer, indicative of systemic inflammation, decreased after r-hIL-7. Increases of colonic mucosal T-cells correlated strongly with the decreased systemic levels of sCD14, the LPS coreceptor - a marker of monocyte activation. Furthermore, the proportion of inflammatory monocytes expressing CCR2 was decreased, as was the basal IL-1β production of peripheral blood monocytes. These data suggest that administration of r-hIL-7 improves the gut mucosal abnormalities of chronic HIV infection and attenuates the systemic inflammatory and coagulation abnormalities that have been linked to it.
尽管接受了抗逆转录病毒疗法（ART），一些HIV感染者外周血和肠道黏膜中的CD4(+) T细胞计数仍低于正常水平。这种不完全的免疫恢复与更高水平的免疫激活相关，表现为生物标志物（包括sCD14和D-二聚体）的全身水平升高，这些是HIV感染发病率和死亡率的独立预测指标。在这项为期12周的单臂、开放标签研究中，我们测试了IL-7辅助疗法对23名接受ART治疗但CD4(+) T细胞恢复不完全的HIV感染者外周血和肠道黏膜中T细胞重建的疗效，使用了一个周期（由三次皮下注射组成）的20 μg/kg重组人IL-7（r-hIL-7）。给予IL-7导致外周血中CD4(+)和CD8(+) T细胞均增加，重要的是，表达肠道归巢整合素α4β7的T细胞也有所扩增。在研究基线和治疗后接受直肠乙状结肠活检的参与者，通过流式细胞术和免疫组织化学检测发现肠道黏膜中的T细胞增加。IL-7治疗还导致肠道屏障完整性明显改善，表现为在给予IL-7 12周后直肠乙状结肠固有层中性粒细胞浸润减少。这还伴随着固有层中TNF减少和FOXP3表达增加。r-hIL-7后，指示全身炎症的血浆sCD14和D-二聚体水平降低。结肠黏膜T细胞的增加与sCD14全身水平降低密切相关，sCD14是单核细胞激活的标志物——脂多糖共受体。此外，表达CCR2的炎性单核细胞比例降低，外周血单核细胞的基础IL-1β产生也降低。这些数据表明，给予r-hIL-7可改善慢性HIV感染的肠道黏膜异常，并减轻与之相关的全身炎症和凝血异常。
