HIV-infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+ T cell activation, and increased risk of non-AIDS morbidity and mortality.
HIV-infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+ T cell activation, and increased risk of non-AIDS morbidity and mortality.
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DOI：
10.1371/journal.ppat.1004078
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发表时间：
2014-05
期刊：
影响因子：
6.7
通讯作者：
Deeks SG
中科院分区：
文献类型：
--
作者：
Serrano-Villar S;Sainz T;Lee SA;Hunt PW;Sinclair E;Shacklett BL;Ferre AL;Hayes TL;Somsouk M;Hsue PY;Van Natta ML;Meinert CL;Lederman MM;Hatano H;Jain V;Huang Y;Hecht FM;Martin JN;McCune JM;Moreno S;Deeks SG
未感染艾滋病毒的老年人中CD 4/CD 8比率低与发病率和死亡率增加有关。接受有效抗逆转录病毒治疗（ART）的HIV感染成年人的一个子集未能使这一比例正常化，即使在他们达到正常的CD 4 + T细胞计数之后。这种临床表型的免疫学和临床特征仍不明确。使用来自四个不同的临床队列和三个临床试验的数据，我们表明，在其他有效的ART期间，HIV感染成人的低CD 4/CD 8比值（在CD 4计数恢复到高于500个细胞/mm 3后）与许多免疫学异常相关，包括从幼稚T细胞向终末分化的CD 8 + T细胞的倾斜T细胞表型，更高水平的CD 8 + T细胞活化（HLADR+ CD 38+）和衰老（CD 28 −和CD 57 + CD 28 −），以及更高的犬尿氨酸/色氨酸比率。外周CD 4/CD 8比值的变化也反映了肠粘膜的变化，但不反映淋巴结的变化。在一项纵向研究中，在感染后6个月内启动ART的个体与较晚启动者（>2年）相比，CD 4/CD 8比率增加更大。在控制了年龄、性别、ART持续时间、最低值和CD 4计数后，CD 4/CD 8比值预测发病率和死亡率的风险增加。因此，在其他有效的ART期间持续低的CD 4/CD 8比率与先天性和适应性免疫激活增加、免疫衰老表型和发病/死亡风险较高相关。这一比例可能被证明是有用的监测响应ART，并可以确定一个独特的子集的个人需要的新的治疗干预措施。CD 4/CD 8比率是与衰老相关的T细胞缺陷集合的标志-“免疫衰老”-并且是一般人群中死亡率的预测因子，在开始ART后具有足够的CD 4 + T细胞恢复的HIV感染个体的重要比例中通常不能正常化。然而，这种临床表型的免疫学和临床特征尚未阐明。在此，我们表明，在治疗的HIV感染，CD 8 + T细胞的扩增，反映为一个低的CD 4/CD 8的比例，确定一个亚组的个人与一些免疫异常和预后不良。这些受试者表现出先天性和适应性免疫激活增加、免疫衰老表型、肠粘膜中的CD 4+和CD 8+失衡以及发病率和死亡率的较高风险。相比之下，那些正常化CD 4/CD 8比率的人具有健康免疫系统的特征。我们观察到，早期ART启动可能有助于更快和更强大的CD 4/CD 8比值正常化相比，较晚的启动。因此，CD 4/CD 8比值可能有助于进一步区分成功治疗的HIV感染者的疾病进展风险，并且对ART的成功应答可能需要外周CD 4 + T细胞计数和CD 4+与CD 8 + T细胞计数的比值正常化。
A low CD4/CD8 ratio in elderly HIV-uninfected adults is associated with increased morbidity and mortality. A subset of HIV-infected adults receiving effective antiretroviral therapy (ART) fails to normalize this ratio, even after they achieve normal CD4+ T cell counts. The immunologic and clinical characteristics of this clinical phenotype remain undefined. Using data from four distinct clinical cohorts and three clinical trials, we show that a low CD4/CD8 ratio in HIV-infected adults during otherwise effective ART (after CD4 count recovery above 500 cells/mm3) is associated with a number of immunological abnormalities, including a skewed T cell phenotype from naïve toward terminally differentiated CD8+ T cells, higher levels of CD8+ T cell activation (HLADR+CD38+) and senescence (CD28− and CD57+CD28−), and higher kynurenine/tryptophan ratio. Changes in the peripheral CD4/CD8 ratio are also reflective of changes in gut mucosa, but not in lymph nodes. In a longitudinal study, individuals who initiated ART within six months of infection had greater CD4/CD8 ratio increase compared to later initiators (>2 years). After controlling for age, gender, ART duration, nadir and CD4 count, the CD4/CD8 ratio predicted increased risk of morbidity and mortality. Hence, a persistently low CD4/CD8 ratio during otherwise effective ART is associated with increased innate and adaptive immune activation, an immunosenescent phenotype, and higher risk of morbidity/mortality. This ratio may prove useful in monitoring response to ART and could identify a unique subset of individuals needed of novel therapeutic interventions. The CD4/CD8 ratio, a hallmark of the collection of T cell defects related to aging –“immunosenescence”- and a predictor of mortality in the general population, often fails to normalize in an important proportion of HIV-infected individuals with adequate CD4+ T cell recovery after ART initiation. However, the immunological and clinical characteristics of this clinical phenotype have not been elucidated. Herein we show that during treated HIV infection, expansion of CD8+ T cells, reflected as a low CD4/CD8 ratio, identifies a subgroup of individuals with a number of immunological abnormalities and a poor prognosis. These subjects exhibit increased innate and adaptive immune activation, an immunosenescent phenotype, CD4+ and CD8+ imbalance in the gut mucosa and higher risk of morbidity and mortality. In contrast, those who normalize the CD4/CD8 ratio have traits of a healthy immune system. We observed that early ART initiation might contribute to more rapid and robust CD4/CD8 ratio normalization compared to later initiation. Hence, the CD4/CD8 ratio might help to further discriminate the risk of disease progression of successfully treated HIV-infected individuals, and a successful response to ART may require both normalization of the peripheral CD4+ T cell count and the ratio of CD4+ to CD8+ T cell counts.
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影响因子：
6.7
作者：
Chevalier MF;Petitjean G;Dunyach-Rémy C;Didier C;Girard PM;Manea ME;Campa P;Meyer L;Rouzioux C;Lavigne JP;Barré-Sinoussi F;Scott-Algara D;Weiss L
通讯作者：
Weiss L
影响因子：
11.8
作者：
Guaraldi, Giovanni;Orlando, Gabriella;Palella, Frank
通讯作者：
Palella, Frank
影响因子：
6.4
作者：
Hatano, Hiroyu;Hayes, Timothy L.;Deeks, Steven G.
通讯作者：
Deeks, Steven G.
影响因子：
20.3
作者：
Brenchley, JM;Karandikar, NJ;Koup, RA
通讯作者：
Koup, RA
影响因子：
4.4
作者：
Hadrup, SR;Strindhall, J;Wikby, A
通讯作者：
Wikby, A