Ferrando-Martinez Sara, De Pablo-Bernal Rebeca S, De Luna-Romero Marta, De Ory Santiago J, Genebat Miguel, Pacheco Yolanda M, Parras Francisco J, Montero Marta, Blanco Jose Ramón, Gutierrez Felix, Santos Jesus, Vidal Francisco, Koup Richard A, Muñoz-Fernández María Ángeles, Leal Manuel, Ruiz-Mateos Ezequiel
Immunology Laboratory, Vaccine Research Center, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Laboratory of Immunovirology, Institute of Biomedicine of Seville, Virgen del Rocío University Hospital/CSIC/University of Seville, Spain.
Clin Infect Dis. 2017 May 1;64(9):1191-1197. doi: 10.1093/cid/cix095.
Thymic function has been mainly analyzed with surrogate peripheral markers affected by peripheral T-cell expansion, making it difficult to assess the role of thymic failure in human immunodeficiency virus (HIV) disease progression. The assay of signal-joint/DβJβ T-cell rearrangement excision circles (sj/β-TREC ratio) overcomes this limitation but has only been assayed in small cohorts. Thus, the aim of this study was to determine the role of thymic function, measured by the sj/β-TREC ratio, on CD4 T-cell maintenance in prospective HIV cohorts that include patients with a wide age range and different immunological phenotypes.
Seven hundred seventy-four patients including typical progressors, long-term nonprogressors (LTNPs), and vertically HIV-infected subjects were analyzed. Thymic function was quantified in peripheral blood samples using the sj/β-TREC ratio. Associations between thymic function and CD4 T-cell dynamics and combination antiretroviral therapy (cART) onset were analyzed using linear, logistic, and Cox proportional hazard models.
Thymic function failure (sj/β-TREC ratio <10) was independently associated with HIV progression. In agreement, patients with distinctive high CD4 T-cell levels and low progression rates (vertically HIV-infected patients and LTNPs, including HIV controllers) had significantly higher thymic function levels whereas patients with thymic function failure had lower CD4 T-cell levels, lower nadir, and faster CD4 T-cell decay.
This work establishes the relevance of thymic function, measured by sj/β-TREC ratio, in HIV disease progression by analyzing a large number of patients in 3 cohorts with different HIV disease progression phenotypes. These results support and help to understand the mechanisms underlying the rationale of early cART onset.
胸腺功能主要通过受外周T细胞扩增影响的替代外周标志物进行分析，这使得评估胸腺功能衰竭在人类免疫缺陷病毒（HIV）疾病进展中的作用变得困难。信号连接/DβJβ T细胞重排切除环（sj/β-TREC比值）检测克服了这一局限性，但仅在小队列中进行过检测。因此，本研究的目的是通过sj/β-TREC比值测定胸腺功能，以确定其在包括不同年龄范围和不同免疫表型患者的前瞻性HIV队列中对CD4 T细胞维持的作用。
对774例患者进行分析，包括典型进展者、长期无进展者（LTNP）和垂直感染HIV的受试者。使用sj/β-TREC比值对外周血样本中的胸腺功能进行定量。采用线性、逻辑和Cox比例风险模型分析胸腺功能与CD4 T细胞动态变化以及联合抗逆转录病毒疗法（cART）开始之间的关联。
胸腺功能衰竭（sj/β-TREC比值<10）与HIV进展独立相关。同样，CD4 T细胞水平高且进展率低的患者（垂直感染HIV的患者和LTNP，包括HIV控制者）胸腺功能水平显著更高，而胸腺功能衰竭的患者CD4 T细胞水平更低、最低点更低且CD4 T细胞衰减更快。
本研究通过分析3个具有不同HIV疾病进展表型队列中的大量患者，证实了通过sj/β-TREC比值测定的胸腺功能在HIV疾病进展中的相关性。这些结果支持并有助于理解早期开始cART的理论基础背后的机制。
