Sino-French Collaborative Laboratory, Tropical Medicine Institute, Guangzhou University of Chinese Medicine, Guangzhou, China.
Infectious Disease Department, Dongguan People's Hospital, Dongguan, China.
J Acquir Immune Defic Syndr. 2018 Sep 1;79(1):126-134. doi: 10.1097/QAI.0000000000001769.
sCD163, a biomarker of monocyte-macrophage activation, has been identified as a predictor of all-cause mortality in treated HIV-infected individuals. Nevertheless, little is known about whether different antiretroviral drugs differentially regulate sCD163 levels and monocyte activation.
A total of 123 patients receiving zidovudine (ZDV)-based (n = 55) or tenofovir disoproxil fumarate (TDF)-based (n = 68) antiretroviral regimens were enrolled, and their viral loads, CD4 counts, as well as plasma sCD163 and sCD14 levels were quantified. Twenty-eight (14 in each group) patients donated additional blood samples for flow cytometry and gene expression analyses using purified monocytes. THP-1 cultures were also used to investigate the effect of ZDV on ADAM17, which is responsible for CD163 shedding.
As compared to the TDF-treated group, the ZDV-treated group had lower plasma sCD163 levels and higher CD163 expression on CD14++CD16 monocytes. Five metabolic-inflammatory genes exhibited significantly different expression levels between purified monocytes of the ZDV and TDF groups (IL-6, 2.90-fold lower in ZDV group, P < 0.001; iNOS, 1.81-fold higher; CX3CR1, 1.72-fold lower; MIP-1β, 1.10-fold lower; and PPARγ-1, 1.36-fold higher, P < 0.05). Moreover, we show that ZDV treatment increases the surface expression of CD163 in cultured THP-1 cells, accompanied by the inhibition of glycosylation and surface expression of ADAM17.
Compared with TDF treatment, ZDV treatment causes lower plasma sCD163 levels, probably by inhibiting the glycosylation of ADAM17 and CD163 shedding. Our results show that ZDV functions as an ADAM17 inhibitor in vivo and extend our understanding of its immune-modulatory effects and adverse effects.
sCD163 是单核细胞-巨噬细胞活化的生物标志物，已被确定为治疗后 HIV 感染个体全因死亡率的预测指标。然而，对于不同的抗逆转录病毒药物是否会对 sCD163 水平和单核细胞活化产生不同的调节作用，人们知之甚少。
共纳入 123 名接受齐多夫定（ZDV）（n = 55）或替诺福韦二吡呋酯（TDF）（n = 68）抗逆转录病毒治疗方案的患者，并定量检测其病毒载量、CD4 计数以及血浆 sCD163 和 sCD14 水平。28 名（每组各 14 名）患者捐献了额外的血液样本，用于使用纯化单核细胞进行流式细胞术和基因表达分析。还使用 THP-1 培养物研究 ZDV 对负责 CD163 脱落的 ADAM17 的影响。
与 TDF 治疗组相比，ZDV 治疗组的血浆 sCD163 水平较低，CD14++CD16 单核细胞上的 CD163 表达较高。在 ZDV 和 TDF 组的纯化单核细胞之间，有 5 个代谢炎症基因表现出明显不同的表达水平（IL-6，ZDV 组低 2.90 倍，P < 0.001；iNOS，高 1.81 倍；CX3CR1，低 1.72 倍；MIP-1β，低 1.10 倍；PPARγ-1，高 1.36 倍，P < 0.05）。此外，我们表明 ZDV 治疗可增加培养的 THP-1 细胞表面 CD163 的表达，同时抑制 ADAM17 和 CD163 糖基化和表面表达。
与 TDF 治疗相比，ZDV 治疗导致血浆 sCD163 水平降低，可能是通过抑制 ADAM17 的糖基化和 CD163 的脱落。我们的结果表明，ZDV 在体内作为 ADAM17 抑制剂发挥作用，并扩展了我们对其免疫调节作用和不良反应的理解。
