第一型疱疹病毒本身以及宿主體內的因子皆能夠調控病毒的感染而影響病毒引起疾病的嚴重性，例如病毒在免疫缺陷病人建立持續性感染。透過小鼠實驗也可以發現第一型疱疹病毒能夠潛伏在健康的小鼠和在免疫缺陷的小鼠上建立持續性感染。病毒的thymidine kinase (TK)被認為是在免疫缺陷小鼠的神經組織中建立持續性感染最重要的因子，因為缺乏病毒TK和UL24的病毒只能夠在嚴重複合型免疫缺失小鼠的眼睛而無法在三叉神經以及腦幹的神經組織建立持續性感染。我們發現在感染缺乏TK病毒小鼠的三叉神經與腦幹有CD4和CD8 T細胞的浸潤，因此我們使用了三種基因改造(TK缺陷或是TK和UL24皆缺陷)的變異病毒以及兩種T細胞剔除小鼠之成鼠來探討第一型疱疹病毒的TK和宿主T細胞在病毒於神經組織中建立持續性感染所扮演的角色。結果顯示在感染變異病毒28天後，三種變異的病毒都能夠在T細胞剔除小鼠的三叉神經和腦幹中分別以高達100%和93%的比例建立持續性感染。根據結果推論宿主的T細胞能夠阻斷第一型疱疹病毒在老鼠的神經組織中建立持續性感染，而且病毒的TK在免疫缺陷小鼠建立持續性感染的過程並非必要因子。因為在神經組織中也可以測到比眼睛還要高的病毒濃度，此外病毒的膜蛋白B(晚期抗原)也能夠在感染TK缺陷病毒之T細胞剔除鼠的腦幹神經細胞裡被偵測到，由這兩個發現推論，成鼠的神經細胞能夠支持TK缺陷病毒的複製。除了病毒因子之外，我們也同時探討控制第一型疱疹病毒感染的細胞因子。在所有第一型疱疹病毒所引起的疾病中，疱疹性腦炎最為致命。我們的小鼠研究發現凝血酶調節素的一個區域可以控制第一型疱疹病毒引起之腦炎的嚴重程度。目前我們仍持續在探討凝血酶調節素的一個區域如何去影響腦炎的發展進程。

Both viral and host factors can modulate herpes simplex virus 1 (HSV-1) infection, which causes serious problems, especially in immunocompromised patients with persistent infection. In consistent with humans, HSV-1 establishes latency in immunocompetent mice and persistent infection in immunocompromised mice. Viral thymidine kinase (TK) is shown to be essential for virus to establish persistent infection in neural tissues of immunocompromised mice, as the mutant virus with defects in both TK and UL24 is detected in the eye, but not in the trigeminal ganglion and brain stem, of severe combined immunodeficiency mice one month after infection. We detected the infiltration of CD4 and CD8 T cells into the trigeminal ganglion and brain stem of mice infected with a TK-negative mutant. Therefore the present study was designated to investigate the importance of viral TK and host T cells for HSV-1 to persist in neural tissues using three genetically engineered mutant viruses with defects in TK or in both TK and UL24 to infect two backgrounds of adult nude mice. All three mutant viruses could establish persistent infection in the brain stems and trigeminal ganglia of nude mice with frequencies up to 100% and 93%, respectively 28 days after infection. Thus, host T cells block HSV-1 persistent infection in mouse neural tissues, and viral TK is dispensable for virus to establish persistent infection in immunocompromised mice. Furthermore, a high viral titer was detected in neural tissues compared with the eye. Viral glycoprotein B, a true late antigen, was detected in brainstem neurons of nude mice persistently infected with the TK-negative mutant. These two findings suggest that adult mouse neurons can support the replication of TK-negative HSV-1. In addition to viral factors, we also search the host factors controlling HSV-1 infection. Our mouse study found that the domain of thrombomodulin regulates the severity of virus-induced encephalitis, which is the most devastating consequence of infection. We are currently searching how the thrombomodulin domain influences the progression of encephalitis.

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