John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
J Virol. 2024 Nov 19;98(11):e0125824. doi: 10.1128/jvi.01258-24. Epub 2024 Oct 21.
Herpes simplex virus 1 (HSV-1) is a significant pathogen that establishes lifelong latent infections with intermittent episodes of resumed disease. In mouse models of HSV infection, sporadic low-level lytic gene expression has been detected during latency in the absence of reactivation events that lead to production of new viruses. This viral activity during latency has been reported using a sensitive Cre-marking model for several lytic gene promoters placed in one location in the HSV-1 genome. Here, we extend these findings in the same model by examining first, the activity of an ectopic lytic gene promoter in several places in the genome and second, whether any promoters might be active in their natural context. We found that expression was detected during latency from ectopic and native promoters, but only in locations near the ends of the unique long genome segment. This location is significant because it is in close proximity to the region from which latency-associated transcripts (LATs) are derived. These results show that native HSV-1 lytic gene promoters can produce protein products during latency, but that this activity is only detectable when they are located close to the LAT locus.IMPORTANCEHSV is a significant human pathogen and the best studied model of mammalian virus latency. Traditionally, the active (lytic) and inactive (latent) phases of infection were considered to be distinct, but the notion of latency being entirely quiescent is evolving due to the detection of some lytic gene expression during latency. Here, we add to this literature by finding that the activity can be found for native lytic gene promoters as well as for constructs placed ectopically in the HSV genome. However, this activity was only detectable when these promoters were located close by a region known to be transcriptionally active during latency. These data have implications for our understanding of HSV gene regulation during latency and the extent to which transcriptionally active regions are insulated from adjacent parts of the viral genome.
单纯疱疹病毒 1（HSV-1）是一种重要的病原体，它会建立终身潜伏感染，并伴有间歇性疾病复发。在 HSV 感染的小鼠模型中，在潜伏期间，即使没有导致新病毒产生的重新激活事件，也会检测到散发性低水平的裂解基因表达。在该病毒基因组的一个位置处，通过使用几个置于裂解基因启动子的敏感 Cre 标记模型，已经报道了这种潜伏期间的病毒活性。在此，我们通过首先检查基因组中几个位置处异位裂解基因启动子的活性，其次检查任何启动子是否可能在其自然环境中具有活性，在相同模型中扩展了这些发现。我们发现，在潜伏期间，从异位和天然启动子检测到了表达，但仅在靠近独特长基因组片段末端的位置。这个位置很重要，因为它靠近潜伏相关转录物（LAT）衍生的区域。这些结果表明，天然 HSV-1 裂解基因启动子可以在潜伏期间产生蛋白产物，但只有当它们靠近 LAT 基因座时，这种活性才可以检测到。重要性 HSV 是一种重要的人类病原体，也是哺乳动物病毒潜伏的研究最充分的模型。传统上，感染的活跃（裂解）和不活跃（潜伏）阶段被认为是截然不同的，但由于在潜伏期间检测到一些裂解基因表达，潜伏完全静止的概念正在发生变化。在此，我们通过发现天然裂解基因启动子以及在 HSV 基因组中异位放置的构建体都可以发挥作用，为该文献做出了贡献。然而，只有当这些启动子靠近在潜伏期间转录活跃的已知区域时，这种活性才可以检测到。这些数据对于我们理解 HSV 基因在潜伏期间的调控以及转录活跃区域与病毒基因组的相邻部分隔离的程度具有重要意义。
