Tincati Camilla, Merlini Esther, Braidotti Paola, Ancona Giuseppe, Savi Federica, Tosi Delfina, Borghi Elisa, Callegari Maria Luisa, Mangiavillano Benedetto, Barassi Alessandra, Bulfamante Gaetano, d'Arminio Monforte Antonella, Romagnoli Solange, Chomont Nicolas, Marchetti Giulia
aClinic of Infectious Diseases bDepartment of Health Sciences, University of Milan cSan Paolo University Hospital, Milan dPathology Unit eMicrobiology Laboratory fBiotechnology Research Centre, Sacred Heart Catholic University, Cremona, Italy gGastroenterology Unit hBiochemistry Laboratory iRoche Innovation Center, Penzberg, Germany jVaccine and Gene Therapy Institute Florida, Port St Lucie, Florida, USA kCentre de Recherche du CHUM et Université de Montréal, Département de Microbiologie, Infectiologie et Immunologie, Montreal, Quebec, Canada.
AIDS. 2016 Apr 24;30(7):991-1003. doi: 10.1097/QAD.0000000000001015.
HIV-infected individuals with incomplete CD4⁺ T-cell recovery upon combination antiretroviral therapy (cART) display high levels of immune activation and microbial translocation. However, whether a link exists between gut damage and poor immunological reconstitution remains unknown.
Cross-sectional study of the gastrointestinal tract in late cART-treated HIV-infected individuals: 15 immunological nonresponders (CD4⁺ <350 cells/μl and/or delta CD4⁺ change from baseline <30%); 15 full responders (CD4⁺ >350 cells/μl and/or delta CD4⁺ change from baseline >30%).
We assessed gut structure (junctional complex proteins in ileum and colon) and function (small intestine permeability/damage and microbial translocation parameters). The composition of the fecal microbiome and the size of the HIV reservoir in the gut and peripheral blood were investigated as possible mechanisms underlying mucosal impairment.
Markers of intestinal permeability, damage, systemic inflammation, and microbial translocation were comparable in all study individuals, yet the expression of junctional complex proteins in gut biopsies was significantly lower in HIV-infected patients with incomplete CD4⁺ restoration and negatively correlated with markers of CD4⁺ reconstitution. Electron microscopy revealed dilated intercellular spaces in individuals lacking immunological response to cART, yet not in patients displaying CD4⁺ T-cell recovery. Analysis of the fecal microbiome revealed an overall outgrowth of Bacteroides-Prevotella spp. with no differences according to CD4⁺ T-cell reconstitution. Interestingly, HIV reservoirs in peripheral CD4⁺ T cells and intestinal tissue negatively correlated with immune recovery.
These observations establish gut damage and the size of the HIV reservoir as features of deficient immunological response to cART and provide new elements for interventional strategies in this setting.
接受联合抗逆转录病毒疗法（cART）后CD4⁺T细胞恢复不完全的HIV感染者表现出高水平的免疫激活和微生物易位。然而，肠道损伤与免疫重建不良之间是否存在关联仍不清楚。
对接受cART治疗的晚期HIV感染者的胃肠道进行横断面研究：15名免疫无应答者（CD4⁺<350个细胞/μl和/或CD4⁺较基线变化<30%）；15名完全应答者（CD4⁺>350个细胞/μl和/或CD4⁺较基线变化>30%）。
我们评估了肠道结构（回肠和结肠中的连接复合体蛋白）和功能（小肠通透性/损伤和微生物易位参数）。研究了粪便微生物群的组成以及肠道和外周血中HIV储存库的大小，作为黏膜损伤的潜在机制。
所有研究个体的肠道通透性、损伤、全身炎症和微生物易位标志物相当，但CD4⁺恢复不完全的HIV感染者肠道活检中连接复合体蛋白的表达明显较低，且与CD4⁺重建标志物呈负相关。电子显微镜显示，对cART无免疫应答的个体细胞间隙扩张，而CD4⁺T细胞恢复的患者则没有。粪便微生物群分析显示拟杆菌-普雷沃菌属总体增多，根据CD4⁺T细胞重建情况无差异。有趣的是，外周CD4⁺T细胞和肠道组织中的HIV储存库与免疫恢复呈负相关。
这些观察结果表明肠道损伤和HIV储存库大小是对cART免疫应答不足的特征，并为该情况下的干预策略提供了新的依据。
