Centre for Experimental Pathogen Host Research, School of Medicine, University College Dublin, Dublin 4, Ireland.
Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, N20, W10, Kita-ku, Sapporo, 001-0020, Japan.
AIDS Res Ther. 2020 Apr 15;17(1):13. doi: 10.1186/s12981-020-00269-0.
The objectives of this study were to investigate the relationships between polymorphisms at the interferon lambda (IFNL) locus and CD4:CD8 ratio normalisation in people living with HIV (PLWH) on effective antiretroviral therapy (ART); and to examine whether these polymorphisms influence the composition of T lymphocyte compartments in long-term treated HIV-1 infection.
A cross-sectional study in PLWH enrolled into the Mater Immunology study. We performed IFNL genotyping on stored samples and evaluated the association of IFNL single-nucleotide polymorphisms (rs368234815 and rs12979860) with CD4:CD8 ratio normalization (> 1) and expanded CD4 and CD8 T-cell subsets; CD45ROCD62L (central-memory), CD45RO CD62L(effector-memory) and CD45ROCD62L (naïve), using logistic and linear regression models, respectively.
190 ambulatory PLWH recruited to the main study, 143 were included in the analysis (38 had no stored DNA and 9 no T-lymphocyte subpopulation). Of 143 included, the median age (IQR) was 45(39-48) years, 64% were male and 66% were of Caucasian ethnicity. Heterosexual-contact (36%), injecting drug-use (33%) and men who have sex with men (24%) were the most presented HIV-transmission risk groups. The majority of subjects (90.2%) were on ART with 79% of the cohort having an undetectable HIV-RNA (< 40 copies/ml) and the time since ART initiation was 7.5 (3.7-10.4) year. rs368234815 and rs12979860 displayed similar allelic frequencies, with minor alleles ΔG and T representing 39% and 42%, respectively, of circulating alleles. rs368234815 ΔG/ΔG minor homozygotes were significantly associated with increased odds for attaining a normalised CD4:CD8 ratio compared to rs368234815 T/T major homozygotes in PLWH virologically suppressed on effective ART (OR = 3.11; 95% CI [1.01:9.56]). rs368234815 ΔG/ΔG homozygosity was also significantly associated with lower levels of CD4 effector memory T-cells (regression coefficient: - 7.1%, p = 0.04) and CD8 naïve T-cell subsets were significantly higher in HIV-1 mono-infected PLWH with rs368234815 ΔG/ΔG (regression coefficient: + 7.2%, p = 0.04).
In virally-suppressed, long-term ART-treated PLWH, rs368234815 ΔG/ΔG homozygotes were more likely to have attained normalisation of their CD4:CD8 ratio, displayed lower CD4 effector memory and higher naive CD8 T-cells. Further studies are needed to replicate our findings in other, larger and more diverse cohorts and to determine the impact of IFNL genetic-variation on CD4:CD8 ratio normalisation and clinical outcomes in PLWH.
本研究旨在探讨干扰素 lambda (IFNL) 基因座多态性与接受有效抗逆转录病毒治疗 (ART) 的 HIV 感染者 (PLWH) 中 CD4:CD8 比值正常化之间的关系；并研究这些多态性是否会影响长期 HIV-1 感染中 T 淋巴细胞亚群的组成。
本研究为 Mater Immunology 研究中的一项横断面研究。我们对存储样本进行 IFNL 基因分型，并使用逻辑回归和线性回归模型评估 IFNL 单核苷酸多态性 (rs368234815 和 rs12979860) 与 CD4:CD8 比值正常化 (>1) 和扩展的 CD4 和 CD8 T 细胞亚群的相关性；CD45ROCD62L（中央记忆）、CD45RO CD62L（效应记忆）和 CD45ROCD62L（幼稚）。
190 名在主要研究中接受门诊治疗的 PLWH 中，有 143 名被纳入分析（38 名无存储 DNA，9 名无 T 淋巴细胞亚群）。在纳入的 143 名患者中，中位年龄（IQR）为 45(39-48) 岁，64%为男性，66%为白种人。异性接触（36%）、注射吸毒（33%）和男男性接触（24%）是最常见的 HIV 传播风险群体。大多数患者（90.2%）正在接受 ART 治疗，79%的患者 HIV-RNA 无法检测到（<40 拷贝/ml），ART 开始时间为 7.5（3.7-10.4）年。rs368234815 和 rs12979860 显示出相似的等位基因频率，其中 minor 等位基因 ΔG 和 T 分别代表循环等位基因的 39%和 42%。与 rs368234815 T/T 主要纯合子相比，rs368234815 ΔG/ΔG 小型纯合子在病毒学抑制的有效 ART 治疗的 PLWH 中获得正常 CD4:CD8 比值的可能性显著更高（OR=3.11；95%CI [1.01:9.56]）。rs368234815 ΔG/ΔG 同型合子也与较低水平的 CD4 效应记忆 T 细胞显著相关（回归系数：-7.1%，p=0.04），而在 rs368234815 ΔG/ΔG 的 HIV-1 单感染 PLWH 中，CD8 幼稚 T 细胞亚群显著更高（回归系数：+7.2%，p=0.04）。
在病毒抑制、长期接受 ART 治疗的 PLWH 中，rs368234815 ΔG/ΔG 同型合子更有可能实现 CD4:CD8 比值的正常化，表现为较低的 CD4 效应记忆和较高的幼稚 CD8 T 细胞。需要进一步的研究来在其他更大、更多样化的队列中复制我们的发现，并确定 IFNL 遗传变异对 PLWH 中 CD4:CD8 比值正常化和临床结果的影响。
