Latent Herpes Simplex Virus 1 Infection Does Not Induce Apoptosis in Human Trigeminal Ganglia

Abstract

(3-5), and, at the same time, in promoting neuronal survival after HSV-1 infection by reducing apoptosis (6). In vitro, the antiapoptotic effects of LAT are mediated by the inhibition of caspase-3, -8,-and -9-induced apoptosis (7,8). In humans and animal models, CD8ϩ T cells are found in latently infected ganglia (9, 10). These CD8 ϩ T cells have been shown to release lytic granules containing granzyme B (GrB) in humans (9, 11) and mice (12, 13). In the setting of HSV-1 latency, rather than inducing apoptosis, GrB cleaves infected-cell polypeptide 4 (ICP4) (13), an essential viral protein needed for viral gene expression, thereby preventing viral reactivation (14). It is a wellknown clinical phenomenon that even after multiple reactivations of HSV-1 in the TG, no sensory deficits occur. Here we investigate if this observation is mirrored by the patho-anatomical findings in human TG latently infected with HSV-1.Human TG were obtained at autopsy at Ludwig Maximilians University (Munich, Germany) with the approval of the Ethics Committee of the Medical Faculty of the University (see Table S1 in the supplemental material). Whole ganglia, including neurons projecting to all three branches, were embedded directly after removal in Jung tissue freezing medium (Leica Microsystems, Nussloch, Germany). Frozen sections of 10 m were cut for immunohistochemistry and in situ hybridization (ISH), while RNA and

The ultimate terminus of evolutional symbiosis leaves a flaw: blinding herpetic stromal keratitis

“…This initial movement develops lifelong HSV-1 latency in nerve growth factor (NGF) reactive A5+ neurons while HSV-2 in contrast is latent in KH10+ neurons [10,11]. The majority of infected neurons survive without apoptosis or necrosis so that sensitivity of the corneal surface remains unchanged during HSV latency in TG [12]. Reactivated HSVs are frequently detectable in tears, saliva or in secretions of the genital tract.…”

“…All these outcomes are supported by epigenetic regulations and innate or acquired immune responses [132][133][134][135]. Functioning neurons in TG are detectable by sensing stimuli on the corneal surface [12]. In mice, HSV DNAs in the TG are detected by in situ hybridization.…”

Keeping it in check: chronic viral infection and antiviral immunity in the brain

“…It has also been speculated that viral RNAs and proteins can contribute to non-lytic outcomes. For instance, HSV latency-associated transcripts inhibit the action and expression of various caspase proteins, which are key mediators of the cell death process 84 . Nevertheless, in some cases, bystander immune-mediated neuronal death may occur.…”

Dendritic cells, CD8<sup>+</sup> T cells and Herpes simplex virus type I latency

“…更值得关注的是, 当利用"保护性"抗原决定簇制作的多肽疫苗免疫人 源化转基因兔后, 相比于"非保护性"的多肽疫苗, 前者 可诱导"保护性"的病毒抗原特异性CD8 + T细胞反应, 赋予免疫动物抵抗致死性病毒攻击的能力 [57] , 且可诱 导更多的"保护性"CD8 + T细胞浸润到TG组织中去, 降 低HSV-1病毒重激活的概率 [7] . [9,12] . 这些CD8 + T细胞大多都拥有活化表型, 也的确产生了正常水平 的含有颗粒酶B和穿孔素的裂解性颗粒 [10] , 但这些裂 解性物质似乎在以一种"非裂解性"的方式作用于受 感染的神经元细胞, 并抑制其中的病毒复制, 尚不清 楚颗粒酶B和穿孔素如何实现这种"非裂解性"的抑制, 但有研究表明, 颗粒酶B可以降解病毒的即刻早期基 因产物ICP4 [58] , 而ICP4对于HSV-1病毒后续基因的表 达至关重要.…”