Background Despite immune restoration after initiation of antiretroviral treatment (ART), the risk of tuberculosis (TB) persists in children living with HIV (CLHIV). We determined patterns of immune restoration of mycobacteria-specific T cells following ART in CLHIV. Methods CD4 and CD8 T cell activation and memory phenotype and functional profiles before and 6 months after ART were evaluated in peripheral blood mononuclear cells (PBMCs) from CLHIV enrolled in the PUSH study (NCT02063880) in Nairobi, Kenya. T cell expression of cytokines and activation induced markers (AIM) were measured following stimulation of PBMCs with a pool of 300 peptides from TB (MTB300) or staphylococcal enterotoxin B (SEB). Results Among 47 CLHIV of median age 1.5 years, SEB-induced Th1 cytokine+ and AIM+ CD4 cell frequencies increased significantly after 6 months ART. Although MTB300-specific CD4 and CD8 cell frequency did not increase after ART, polyfunctional capacity of MTB300-specific CD4 cells expressing combinations of Th1 cytokines with CD40L increased significantly after ART. Baseline age, immune activation, and effector memory CD4 levels were associated with less restoration of MTB300-specific polyfunctional CD4 cells, whereas CD4% and levels of naïve CD4 cells following ART were associated with improved MTB300-specific polyfunctional capacity. Conclusions Despite increases in Th1 cytokine production, deficits in mycobacteria-specific CD4 cells persisted 6 months after ART, with higher deficits in older CLHIV with more immunosuppression, higher immune activation, and lower proportion of naïve CD4 cells. These findings may explain persistent TB risk during early ART among CLHIV and identify those at highest risk.

中文翻译：

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HIV 感染儿童 6 个月抗逆转录病毒治疗后多功能分枝杆菌特异性 T 细胞反应恢复的模式和辅因子


背景 尽管在开始抗逆转录病毒治疗 （ART） 后免疫力恢复，但 HIV 感染儿童 （CLHIV） 患结核病 （TB） 的风险仍然存在。我们确定了 CLHIV 中 ART 后分枝杆菌特异性 T 细胞的免疫恢复模式。方法 在肯尼亚内罗毕参加 PUSH 研究 （NCT02063880） 的 CLHIV 外周血单核细胞 （PBMC） 中评估 ART 前后和 6 个月的 CD4 和 CD8 T 细胞活化和记忆表型和功能特征。用来自 TB （MTB300） 或葡萄球菌肠毒素 B （SEB） 的 300 个肽刺激 PBMC 后，测量细胞因子和活化诱导标志物 （AIM） 的 T 细胞表达。结果 在 47 例中位年龄为 1.5 岁的 CLHIV 中，SEB 诱导的 Th1 细胞因子+ 和 AIM+ CD4 细胞频率在 ART 6 个月后显著增加。尽管 ART 后 MTB300 特异性 CD4 和 CD8 细胞频率没有增加，但 ART 后表达 Th1 细胞因子与 CD40L 组合的 MTB300 特异性 CD4 细胞的多功能能力显著增加。基线年龄、免疫激活和效应记忆 CD4 水平与 MTB300 特异性多功能 CD4 细胞的恢复较少相关，而 ART 后 CD4% 和初始 CD4 细胞水平与 MTB300 特异性多功能能力的改善相关。结论 尽管 Th1 细胞因子产生增加，但分枝杆菌特异性 CD4 细胞的缺陷在 ART 后 6 个月持续存在，老年 CLHIV 的缺陷更高，免疫抑制程度更高，免疫激活程度更高，幼稚 CD4 细胞比例较低。这些发现可以解释 CLHIV 早期 ART 期间持续的 TB 风险，并确定风险最高的人群。