Tinago Willard, Coghlan Elizabeth, Macken Alan, McAndrews Julie, Doak Brenda, Prior-Fuller Charlotte, Lambert John S, Sheehan Gerard J, Mallon Patrick W G
HIV Molecular Research Group, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland; Department of Community Medicine, University of Zimbabwe, Harare, Zimbabwe.
HIV Molecular Research Group, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
PLoS One. 2014 May 9;9(5):e97011. doi: 10.1371/journal.pone.0097011. eCollection 2014.
Although effective antiretroviral therapy(ART) increases CD4+ T-cell count, responses to ART vary considerably and only a minority of patients normalise their CD4+/CD8+ ratio. Although retention of naïve CD4+ T-cells is thought to predict better immune responses, relationships between CD4+ and CD8+ T-cell subsets and CD4+/CD8+ ratio have not been well described.
A cross-sectional study in a cohort of ambulatory HIV+ patients. We used flow cytometry on fresh blood to determine expanded CD4+ and CD8+ T-cell subsets; CD45RO+CD62L+(central memory), CD45RO+CD62L-(effector memory) and CD45RO-CD62L+(naïve) alongside routine T-cell subsets(absolute, percentage CD4+ and CD8+ counts), HIVRNA and collected demographic and treatment data. Relationship between CD4+/CD8+ T-cell ratio and expanded T-cell subsets was determined using linear regression analysis. Results are median[IQR] and regression coefficients unless stated.
We recruited 190 subjects, age 42(36-48) years, 65% male, 65.3% Caucasian, 91% on ART(52.6% on protease inhibitors), 78.4% with HIVRNA<40cps/ml and median ART duration 6.8(2.6-10.2) years. Nadir and current CD4+ counts were 200(112-309) and 465(335-607) cells/mm3 respectively. Median CD4+/CD8+ ratio was 0.6(0.4-1.0), with 26.3% of subjects achieving CD4+/CD8+ ratio>1. Of the expanded CD4+ T-cell subsets, 27.3(18.0-38.3)% were naïve, 36.8(29.0-40.0)% central memory and 27.4(20.0-38.5)% effector memory. Of the CD8+ T-cells subsets, 16.5(10.2-25.5)% were naïve, 19.9(12.7-26.6)% central memory and 41.0(31.8-52.5)% effector memory. In the multivariable adjusted analysis, total cumulative-ART exposure(+0.15,p = 0.007), higher nadir CD4+ count(+0.011,p<0.001) and higher %CD8+ naive T-cells(+0.0085,p<0.001) were associated with higher CD4+/CD8+ ratio, higher absolute CD8+ T-cell(-0.0044,p<0.001) and higher %CD4+ effector memory T-cells(-0.004,p = 0.0036) were associated with lower CD4+/CD8+ ratio. Those with CD4+/CD8+ ratio>1 had significantly higher median %CD8+ naive T-cells; 25.4(14.0-36.0)% versus 14.4(9.4-21.6)%, p<0.0001, but significantly lower absolute CD8+ count; 464(384.5-567) versus 765(603-1084) cells/mm3, p<0.001.
Study suggests important role for naïve CD8+ T-cell populations in normalisation of the immune response to HIV-infection. How these findings relate to persistent immune activation on ART requires further study.
尽管有效的抗逆转录病毒疗法（ART）可提高CD4 + T细胞计数，但对ART的反应差异很大，只有少数患者的CD4 + / CD8 +比值恢复正常。尽管幼稚CD4 + T细胞的保留被认为可预测更好的免疫反应，但CD4 +和CD8 + T细胞亚群与CD4 + / CD8 +比值之间的关系尚未得到充分描述。
对一组门诊HIV +患者进行横断面研究。我们使用新鲜血液上的流式细胞术来确定扩增的CD4 +和CD8 + T细胞亚群；CD45RO + CD62L +（中央记忆）、CD45RO + CD62L -（效应记忆）和CD45RO - CD62L +（幼稚）以及常规T细胞亚群（绝对计数、CD4 +和CD8 +计数百分比）、HIVRNA，并收集人口统计学和治疗数据。使用线性回归分析确定CD4 + / CD8 + T细胞比值与扩增的T细胞亚群之间的关系。结果为中位数[四分位间距]和回归系数，除非另有说明。
我们招募了190名受试者，年龄42（36 - 48）岁，65%为男性，65.3%为白种人，91%接受ART治疗（52.6%接受蛋白酶抑制剂治疗），78.4%的HIVRNA<40拷贝/毫升，ART治疗的中位持续时间为6.8（2.6 - 10.2）年。最低点和当前CD4 +计数分别为200（112 - 309）和465（335 - 607）个细胞/立方毫米。CD4 + / CD8 +比值的中位数为0.6（0.4 - 1.0），26.3%的受试者CD4 + / CD8 +比值>1。在扩增的CD4 + T细胞亚群中，27.3（18.0 - 38.3）%为幼稚细胞，36.8（29.0 - 40.0）%为中央记忆细胞，27.4（20.0 - 38.5）%为效应记忆细胞。在CD8 + T细胞亚群中，16.5（10.2 - 25.5）%为幼稚细胞，19.9（12.7 - 26.6）%为中央记忆细胞，41.0（31.8 - 52.5）%为效应记忆细胞。在多变量调整分析中，总累积ART暴露（+0.15，p = 0.007）、较高的最低点CD4 +计数（+0.011，p<0.001）和较高的CD8 +幼稚T细胞百分比（+0.0085，p<0.001）与较高的CD4 + / CD8 +比值相关，较高的绝对CD8 + T细胞（-0.0044，p<0.001）和较高的CD4 +效应记忆T细胞百分比（-0.004，p = 0.0036）与较低的CD4 + / CD8 +比值相关。CD4 + / CD8 +比值>1的患者CD8 +幼稚T细胞的中位数百分比显著更高；25.4（14.0 - 36.0）%对14.4（9.4 - 21.6）%，p<0.0001，但绝对CD8 +计数显著更低；464（384.5 - 567）对765（603 - 1084）个细胞/立方毫米，p<0.001。
研究表明幼稚CD8 + T细胞群体在HIV感染免疫反应正常化中起重要作用。这些发现与ART上持续的免疫激活之间的关系需要进一步研究。
