Contrasting inflammatory signatures in peripheral blood and bronchoalveolar cells reveal compartment-specific effects of HIV infection

The mechanisms by which HIV increases susceptibility to tuberculosis and other respiratory infections are incompletely understood. We used transcriptomics of paired whole bronchoalveolar lavage (BAL) fluid and peripheral blood mononuclear cells to compare the effect of HIV at the lung mucosal surface and in the peripheral blood. The large majority of HIV-induced differentially expressed genes (DEGs) were specific to either the peripheral or lung mucosa compartments (1,307/1,404, 93%). Type I interferon signaling was the dominant signature of DEGs in HIV-positive blood with a less dominant and qualitatively distinct type I interferon gene set expression pattern in HIV-positive BAL. DEGs in the HIV-positive BAL were significantly enriched for infiltration with cytotoxic CD8+ T cells. Higher expression of representative transcripts and proteins in BAL CD8+ T cells during HIV infection, including IFNG (IFN-?), GZMB (Granzyme B) and PDCD1 (PD-1), was confirmed by cell-subset specific transcriptional analysis and flow cytometry. Thus, we report that a whole transcriptomic approach revealed qualitatively distinct effects of HIV in blood and bronchoalveolar compartments. Further work exploring the impact of distinct type I interferon programs and CD8+ T cells infiltration of the lung mucosa during HIV infection may provide novel insights into HIV-induced susceptibility to respiratory pathogens. Overall design: Transcriptional profilling of paired BAL and PBMCs samples from HIV negative and HIV positive individuals

人类免疫缺陷病毒（Human Immunodeficiency Virus, HIV）增加结核病与其他呼吸道感染易感性的具体机制尚未完全明确。本研究对配对的全支气管肺泡灌洗液（bronchoalveolar lavage fluid, BAL）与外周血单个核细胞开展转录组学分析，以对比HIV在肺黏膜表面与外周血中的作用效应。绝大多数HIV诱导的差异表达基因（differentially expressed genes, DEGs）仅特异性表达于外周血或肺黏膜腔室（1,307/1,404，93%）。HIV阳性外周血样本中DEGs的核心特征为I型干扰素信号通路激活，而HIV阳性BAL样本中I型干扰素基因集的表达模式虽占比更低，但其质性特征存在显著差异。HIV阳性BAL样本中的DEGs显著富集于细胞毒性CD8+ T细胞浸润相关的生物学过程。经细胞亚群特异性转录分析与流式细胞术验证，HIV感染期间BAL来源CD8+ T细胞内代表性转录本与蛋白的表达水平显著升高，涵盖IFNG（IFN-γ）、GZMB（颗粒酶B）与PDCD1（PD-1）等靶点。综上，本研究通过全转录组学分析揭示了HIV在外周血与支气管肺泡腔室中具有质性迥异的作用效应。未来可进一步探究HIV感染期间不同I型干扰素信号程序与肺黏膜CD8+ T细胞浸润的影响，这或将为阐释HIV诱导的呼吸道病原体易感性提供全新研究视角。实验设计：对HIV阴性与HIV阳性个体的配对BAL与外周血单个核细胞（PBMC）样本进行转录组分析。