單純疱疹病毒(Herpes simplex virus, HSV)引起的腦炎是偶發性致死性腦炎中最常見的一種。目前大部分研究控制疱疹病毒腦炎的因子多著重在一些免疫因子或是轉殖基因到老鼠身上研究該基因對控制疱疹病毒腦炎重要性的相關研究。因此，很少有研究指出控制疱疹病毒腦炎相關的內源性細胞因子。在本論文中，我們利用microarray的方式找到一個基因— early growth response 1 (Egr-1)，在神經細胞被疱疹病毒感染的情況下被大量誘發表現。進一步的研究發現，Egr-1的表現可以促進疱疹病毒在神經細胞中的複製，使宿主的死亡率增加。而且，Egr-1可能是藉由調控病毒基因啟動子的活性來促進病毒的複製。因此，在控制及預防致死性疱疹病毒感染方面，Egr-1可能可以用來當作治療的標的。
在病毒感染急性期過後，疱疹病毒會在週邊及中樞神經系統建立潛伏感染，經過適當的刺激病毒會從神經組織中復發。目前病毒在週邊神經結復發的機制已被廣泛的研究，然而病毒在腦部復發的研究卻仍有限。因為以最敏感的ex vitro實驗方法鮮少能觀察到病毒從中樞神經組織中復發的現象。因此，本論文中我們將實驗的方法進行修改後，發現高達88%的腦幹組織培養中可以觀察到有病毒復發的現象，其他腦區亦有程度不等的病毒復發現象。實驗中也發現，病毒復發程度的多寡和病毒在急性期複製數量以及潛伏期時病毒基因組在神經組織中的數量有關。相較於先前的實驗方法，我們所使用的方法能增進神經細胞的存活率。因此，在我們的系統中能看到病毒在中樞神經組織復發的現象。此外，我們也發現到這種現象並非限定在單一病毒或老鼠的品系，甚至第二型疱疹病毒也能觀察到相同的結果。此一發現不但釐清長期以來中樞神經組織是否為HSV潛伏感染組織的爭議，並且所建立的研究模式將可用來探討病毒在中樞神經復發和一些神經性疾病的相關性。
臨床上常發現到疱疹病毒的感染或復發對免疫系統有缺陷的病人，常會造成重大的傷害。針對疱疹病毒的治療方面，目前已有有效抑制病毒複製的抗病毒藥物像是: Acyclovir，Gancyclovir。不過當抗藥性的病毒株出現時，往往在治療上面臨嚴重的問題。常見的抗藥性病毒株大部分都是在thymidine kinase (TK)基因上發生變異。在先前動物模式上的研究指出，TK基因突變的病毒無法在神經細胞複製或是從潛伏狀態復發，不過同時感染野生型和突變的病毒株時，可以從復發的樣本中分離出突變的病毒。臨床上常從病人復發的檢體中同時偵測到野生型和突變的病毒。因此在本論文中我們想要探討究竟是何種機制能使得TK基因突變的病毒復發。實驗結果發現是透過野生型的病毒株提供TK 酵素的補償作用使得突變的病毒復發。並且發現對於病毒在急性期、潛伏期的建立與病毒復發時，突變病毒株所需的TK活性各有不同。

Herpes simplex virus (HSV) induced encephalitis during acute infection is the most common sporadic and life-threatening encephalitis. Current studies investigating the factors which regulate herpetic encephalitis focus on immune factors or the expression of a transgene in mice. There are very few studies investigating endogenous factors which regulate herpetic encephalitis. Therefore, we performed a microarray analysis to determine the alteration of host genes in human neuronal cells during HSV-1 infection. Early growth response 1 (Egr-1), a transcription factor, is found to be up-regulated in HSV-1-infected neuronal cells. Our results show that Egr-1 functions to enhance HSV-1 replication in neuronal cells and consequently increases the mortality rate of infected mice. These results indicate a crucial role of Egr-1 in regulating HSV-1 infection.
Following acute infection, HSV establishes latency in the neurons of both peripheral sensory ganglia and central nervous system (CNS) of latently infected hosts. However, several ex vivo studies have documented that latent HSV reactivates rarely from the CNS of mice when assayed by mincing tissues before explant culture, despite the presence of viral genomes in brain tissues. Therefore, in this study, we modified the reactivation protocol originally used for trigeminal ganglia and observed as high as 88% of viral reactivation from brain stems of latently infected mice. The high reactivation frequency of brain stem correlated with higher levels of acute viral replication and latent viral genomes, and the dissociation method greatly enhanced the cell viability and viral infectivity of brain stem cultures when compared to the conventional mincing method. Lastly, the efficient reactivation of HSV from mouse CNS was observed in more than one viral strain, viral serotype, or mouse strain, further indicating that the CNS can be an authentic latency site for HSV. This model also can serve as a good tool to investigate the potential of HSV to cause recurrent diseases in the CNS.
Acyclovir (ACV) is the most common drug in clinical treatment of HSV infection; however, the emergence of ACV-resistant viruses can hinder therapy and pose a significant problem, particularly, in immunocompromised patients. Many drug-resistant mutants have been reported as thymidine kinase (TK) mutants. Laboratory strains of HSV lacking TK cannot replicate to detectable levels acutely in mouse trigeminal ganglia and do not reactivate from latency. However, many pathogenic clinical isolates that are resistant to the antiviral drug ACV are heterogeneous populations of TK-negative (TK-) and TK-positive (TK+) viruses. In this study, we investigated the reactivation mechanism of TK- HSV. The results showed that TK+ virus permits TK- virus reactivation through enzymatic complementation of TK. The requirement for the amount of TK during acute replication, latency establishment, and reactivation is different.

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