Serrano-Villar Sergio, Sainz Talia, Ma Zhong-Min, Utay Netanya S, Chun Tae-Wook, Mann Surinder, Kashuba Angela D, Siewe Basile, Albanese Anthony, Troia-Cancio Paolo, Sinclair Elizabeth, Somasunderam Anoma, Yotter Tammy, Deeks Steven G, Landay Alan, Pollard Richard B, Miller Christopher J, Moreno Santiago, Asmuth David M
University Hospital Ramón y Cajal, Madrid, Spain.
University Hospital La Paz, Madrid, Spain.
PLoS Pathog. 2016 Jan 21;12(1):e1005381. doi: 10.1371/journal.ppat.1005381. eCollection 2016 Jan.
Whether initiation of antiretroviral therapy (ART) regimens aimed at achieving greater concentrations within gut associated lymphoid tissue (GALT) impacts the level of mucosal immune reconstitution, inflammatory markers and the viral reservoir remains unknown. We included 12 HIV- controls and 32 ART-naïve HIV patients who were randomized to efavirenz, maraviroc or maraviroc+raltegravir, each with fixed-dose tenofovir disoproxil fumarate/emtricitabine. Rectal and duodenal biopsies were obtained at baseline and at 9 months of ART. We performed a comprehensive assay of T-cell subsets by flow cytometry, T-cell density in intestinal biopsies, plasma and tissue concentrations of antiretroviral drugs by high-performance liquid chromatography/mass spectroscopy, and plasma interleukin-6 (IL-6), lipoteichoic acid (LTA), soluble CD14 (sCD14) and zonulin-1 each measured by ELISA. Total cell-associated HIV DNA was measured in PBMC and rectal and duodenal mononuclear cells. Twenty-six HIV-infected patients completed the follow-up. In the duodenum, the quadruple regimen resulted in greater CD8+ T-cell density decline, greater normalization of mucosal CCR5+CD4+ T-cells and increase of the naïve/memory CD8+ T-cell ratio, and a greater decline of sCD14 levels and duodenal HIV DNA levels (P = 0.004 and P = 0.067, respectively), with no changes in HIV RNA in plasma or tissue. Maraviroc showed the highest drug distribution to the gut tissue, and duodenal concentrations correlated well with other T-cell markers in duodenum, i.e., the CD4/CD8 ratio, %CD4+ and %CD8+ HLA-DR+CD38+ T-cells. Maraviroc use elicited greater activation of the mucosal naïve CD8+ T-cell subset, ameliorated the distribution of the CD8+ T-cell maturational subsets and induced higher improvement of zonulin-1 levels. These data suggest that combined CCR5 and integrase inhibitor based combination therapy in ART treatment naïve patients might more effectively reconstitute duodenal immunity, decrease inflammatory markers and impact on HIV persistence by cell-dependent mechanisms, and show unique effects of MVC in duodenal immunity driven by higher drug tissue penetration and possibly by class-dependent effects.
旨在在肠道相关淋巴组织（GALT）中实现更高浓度的抗逆转录病毒疗法（ART）方案的启动是否会影响黏膜免疫重建水平、炎症标志物和病毒储存库仍不清楚。我们纳入了12名HIV阴性对照者和32名未接受过ART的HIV患者，他们被随机分为接受依非韦伦、马拉维罗或马拉维罗+雷特格韦治疗，每种方案均联合固定剂量的富马酸替诺福韦二吡呋酯/恩曲他滨。在基线和ART治疗9个月时获取直肠和十二指肠活检组织。我们通过流式细胞术对T细胞亚群进行了全面检测，通过高效液相色谱/质谱法检测肠道活检组织中的T细胞密度、抗逆转录病毒药物的血浆和组织浓度，并通过酶联免疫吸附测定（ELISA）分别检测血浆白细胞介素-6（IL-6）、脂磷壁酸（LTA）、可溶性CD14（sCD14）和zonulin-1。在PBMC以及直肠和十二指肠单核细胞中检测总细胞相关HIV DNA。26名HIV感染患者完成了随访。在十二指肠中，四联疗法导致CD8 + T细胞密度下降幅度更大，黏膜CCR5 + CD4 + T细胞的正常化程度更高，幼稚/记忆CD8 + T细胞比例增加，sCD14水平和十二指肠HIV DNA水平下降幅度更大（分别为P = 0.004和P = 0.067），而血浆或组织中的HIV RNA没有变化。马拉维罗在肠道组织中的药物分布最高，十二指肠浓度与十二指肠中的其他T细胞标志物，即CD4/CD8比值、%CD4 +和%CD8 + HLA-DR + CD38 + T细胞密切相关。使用马拉维罗可引起黏膜幼稚CD8 + T细胞亚群的更大激活，改善CD8 + T细胞成熟亚群的分布，并使zonulin-1水平有更高的改善。这些数据表明，在未接受过ART治疗的患者中，基于CCR5和整合酶抑制剂的联合治疗可能更有效地重建十二指肠免疫，降低炎症标志物，并通过细胞依赖性机制影响HIV的持续存在，并且显示出马拉维罗在更高药物组织渗透性以及可能的类别依赖性作用驱动的十二指肠免疫中具有独特作用。
