Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI 53716, USA.
Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32611, USA.
Viruses. 2022 Apr 27;14(5):909. doi: 10.3390/v14050909.
HSV-1 is a human pathogen that establishes a lifelong infection in the host. HSV-1 is transported by retrograde axonal transport to sensory neurons in the peripheral nervous system where latent viral genomes can reactivate. The resulting virus travels via anterograde axonal transport to the periphery and can cause clinical disease. CTCF insulators flank the LAT and IE regions of HSV-1 and during latency and maintain the integrity of transcriptional domains through a myriad of functions, including enhancer-blocking or barrier-insulator functions. Importantly, during reactivation, CTCF protein is evicted from the HSV-1 genome, especially from the CTRL2 insulator. CTRL2 is a functional insulator downstream of the 5'exon region of the LAT, so these results suggest that the disruption of this insulator may be required for efficient HSV-1 reactivation. To further explore this, we used a recombinant virus containing a deletion of the CTRL2 insulator (ΔCTRL2) in a rabbit ocular model of HSV-1 infection and induced reactivation. We show that, in the absence of the CTRL2 insulator, HSV-1 established an equivalent latent infection in rabbits, but those rabbits failed to efficiently reactivate from latency. Furthermore, we found a significant decrease in the expression of the gene Us9-, a gene that codes for a type II membrane protein that has been shown to be required for anterograde transport in neurons. Taken together, these results suggest that the functions of the CTRL2 insulator and Us9 activation in reactivating neurons are intrinsically linked through the regulation of a gene responsible for the axonal transport of HSV-1 to the periphery.
单纯疱疹病毒 1 型（HSV-1）是一种在宿主体内建立终身感染的人类病原体。HSV-1 通过逆行轴突运输被运送到周围神经系统中的感觉神经元，潜伏的病毒基因组在那里重新激活。由此产生的病毒通过顺行轴突运输到达外周，并可能导致临床疾病。CTCF 绝缘子侧翼位于 HSV-1 的 LAT 和 IE 区域，在潜伏期内并通过多种功能维持转录域的完整性，包括增强子阻断或屏障绝缘子功能。重要的是，在重新激活期间，CTCF 蛋白从 HSV-1 基因组中被驱逐，特别是从 CTRL2 绝缘子中。CTRL2 是 LAT 5'外显子区域下游的功能性绝缘子，因此这些结果表明，这种绝缘子的破坏可能是 HSV-1 有效重新激活所必需的。为了进一步探索这一点，我们在兔眼 HSV-1 感染模型中使用了一种含有 CTRL2 绝缘子缺失的重组病毒（ΔCTRL2）并诱导了重新激活。我们表明，在缺乏 CTRL2 绝缘子的情况下，HSV-1 在兔子中建立了等效的潜伏感染，但这些兔子未能从潜伏期中有效重新激活。此外，我们发现编码 II 型膜蛋白的基因 Us9 的表达显著下降，该基因已被证明是神经元顺行运输所必需的。综上所述，这些结果表明，CTRL2 绝缘子的功能和 Us9 的激活在重新激活神经元方面是内在相关的，这是通过调节负责 HSV-1 向周围神经轴突运输的基因来实现的。
