Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
EBioMedicine. 2024 May;103:105133. doi: 10.1016/j.ebiom.2024.105133. Epub 2024 Apr 26.
Endogenous retroelements (EREs), including human endogenous retroviruses (HERVs) and long interspersed nuclear elements (LINEs), comprise almost half of the human genome. Our previous studies of the interferome in the gut suggest potential mechanisms regarding how IFNb may drive HIV-1 gut pathogenesis. As ERE activity is suggested to partake in type 1 immune responses and is incredibly sensitive to viral infections, we sought to elucidate underlying interactions between ERE expression and gut dynamics in people living with HIV-1 (PLWH).
ERE expression profiles from bulk RNA sequencing of colon biopsies and PBMC were compared between a cohort of PLWH not on antiretroviral therapy (ART) and uninfected controls.
59 EREs were differentially expressed in the colon of PLWH when compared to uninfected controls (padj <0.05 and FC ≤ -1 or ≥ 1) [Wald's Test]. Of these 59, 12 EREs were downregulated in PLWH and 47 were upregulated. Colon expression of the ERE loci LTR19_12p13.31 and L1FLnI_1q23.1s showed significant correlations with certain gut immune cell subset frequencies in the colon. Furthermore L1FLnI_1q23.1s showed a significant upregulation in peripheral blood mononuclear cells (PBMCs) of PLWH when compared to uninfected controls suggesting a common mechanism of differential ERE expression in the colon and PBMC.
ERE activity has been largely understudied in genomic characterizations of human pathologies. We show that the activity of certain EREs in the colon of PLWH is deregulated, supporting our hypotheses that their underlying activity could function as (bio)markers and potential mediators of pathogenesis in HIV-1 reservoirs.
US NIH grants NCI CA260691 (DFN) and NIAID UM1AI164559 (DFN).
内源性逆转录元件（EREs），包括人类内源性逆转录病毒（HERVs）和长散布核元件（LINEs），占人类基因组的近一半。我们之前对肠道中的干扰素组的研究表明了 IFNb 可能驱动 HIV-1 肠道发病机制的潜在机制。由于 ERE 活性被认为参与了 1 型免疫反应，并且对病毒感染极其敏感，我们试图阐明 HIV-1 感染者（PLWH）肠道动力学与 ERE 表达之间的潜在相互作用。
比较未接受抗逆转录病毒治疗（ART）的 PLWH 和未感染对照者的结肠活检和 PBMC 的批量 RNA 测序的 ERE 表达谱。
与未感染对照者相比，PLWH 结肠中 59 个 ERE 差异表达（padj <0.05，FC ≤-1 或≥1）[Wald 检验]。在这 59 个 ERE 中，有 12 个下调，47 个上调。ERE 基因座 LTR19_12p13.31 和 L1FLnI_1q23.1s 在结肠中的表达与结肠中某些免疫细胞亚群的频率呈显著相关性。此外，与未感染对照者相比，PLWH 的外周血单核细胞（PBMC）中 L1FLnI_1q23.1s 的表达显著上调，这表明 ERE 在结肠和 PBMC 中的差异表达存在共同的机制。
在人类病理学的基因组特征研究中，EREs 的活性在很大程度上被忽视了。我们表明，PLWH 结肠中某些 ERE 的活性失调，支持了我们的假设，即它们潜在的活性可以作为（生物）标志物和 HIV-1 储库发病机制的潜在介质。
美国 NIH 授予 NCI CA260691（DFN）和 NIAID UM1AI164559（DFN）的资助。
