US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
Henry M. Jackson Foundation for the Advancement of Military Medicine (HJF), Bethesda, Maryland, USA.
J Clin Invest. 2020 Jun 1;130(6):2845-2858. doi: 10.1172/JCI130597.
Plasmacytoid dendritic cells (pDCs) are robust producers of IFNα and one of the first immune cells to respond to SIV infection. To elucidate responses to early HIV-1 replication, we studied blood pDCs in 29 HIV-infected participants who initiated antiretroviral therapy during acute infection and underwent analytic treatment interruption (ATI). We observed an increased frequency of partially activated pDCs in the blood before detection of HIV RNA. Concurrent with peak pDC frequency, we detected a transient decline in the ability of pDCs to produce IFNα in vitro, which correlated with decreased phosphorylation of IFN regulatory factory 7 (IRF7) and NF-κB. The levels of phosphorylated IRF7 and NF-κB inversely correlated with plasma IFNα2 levels, implying that pDCs were refractory to in vitro stimulation after IFNα production in vivo. After ATI, decreased expression of IFN genes in pDCs inversely correlated with the time to viral detection, suggesting that pDC IFN loss is part of an effective early immune response. These data from a limited cohort provide a critical first step in understanding the earliest immune response to HIV-1 and suggest that changes in blood pDC frequency and function can be used as an indicator of viral replication before detectable plasma viremia.
浆细胞样树突状细胞 (pDCs) 是 IFNα 的强大产生者，也是对 SIV 感染作出反应的首批免疫细胞之一。为了阐明对早期 HIV-1 复制的反应，我们研究了 29 名在急性感染期间开始接受抗逆转录病毒治疗并接受分析性治疗中断 (ATI) 的 HIV 感染者血液中的 pDC。我们在检测到 HIV RNA 之前，观察到血液中部分激活的 pDC 频率增加。与 pDC 频率峰值同时发生的是，我们检测到 pDC 体外产生 IFNα 的能力短暂下降，这与 IFN 调节因子 7 (IRF7) 和 NF-κB 的磷酸化减少相关。磷酸化的 IRF7 和 NF-κB 水平与血浆 IFNα2 水平呈负相关，这意味着 pDC 在体内产生 IFNα 后对体外刺激产生抗性。ATI 后，pDC 中 IFN 基因的表达减少与病毒检测时间呈负相关，这表明 pDC IFN 丢失是 HIV-1 早期有效免疫反应的一部分。来自有限队列的数据提供了理解 HIV-1 最早免疫反应的重要第一步，并表明血液 pDC 频率和功能的变化可用于在可检测的血浆病毒血症之前作为病毒复制的指标。
