臺灣博碩士論文加值系統

　　人類被單純?疹病毒感染後，病毒會終身潛伏在神經組織內。
臨床治療病毒的感染大都使用Acyclovir類的藥物去抑制病毒的複製，然而，如此會導致抗藥性的病毒 (通常是thymidine kinase突變株) 的出現而使治療無效，尤其在免疫不全的病人，因此尋找新的治療方式對付抗藥性病毒是十分重要的。過去已知干擾素(包含 .三型干擾素) 具有良好的抗病毒效果，以前的研究曾利用 及 干擾素結合
，可十分有效的對抗野生型單純?疹。因而本篇研究中，我們也利用干擾素結合的方式，嘗試去解決抗藥性病毒的問題。首先在細胞組織培養的實驗中，我們結合不同種類干擾素去抑制病毒在Vero細胞上的生長，發現當結合 及 干擾素時可有效抑制抗藥性病毒的生長達50倍之多，並且在感染前先給比感染後給還要好，相同抑制效果也可在人類的A549細胞株能看到。在小鼠動物實驗中，在感染動物前我們先給小鼠四次結合 及 干擾素治療，之後再感染2×106 PFU的294dltk抗藥性病毒，如此不但能抑制急性期病毒在眼睛複製高達1000倍，而且也抑制潛伏期病毒在三叉神經的復發，從70%復發率降至0%的復發率。
當在感染病毒後給干擾素也有相同的抑制作用，但在感染後越晚給效果越差。此外當感染另一種抗藥性病毒tkLTRZ1 (此病毒需要同時感染野生型病毒才能復發)，結合 及 干擾素不但能抑制病毒急性期在小鼠眼睛、三叉神經及腦幹的生長，也能抑制病毒潛伏期從三叉神經、腦幹及脊神經的復發。為了模擬病毒在免疫不全的宿主身上感染的情形，我們感染了294dltk抗藥性病毒在裸鼠 (nude mice) 身上，當給予結合 及 干擾素治療後的小鼠，病毒在其眼睛生長的情形也能被有效的抑制下來。從以上的結果可知，結合 及 干擾素的治療是一個對付抗藥性?疹病毒的有效治療方式。

　　Herpes simplex virus type 1 infects and establishes latent infection in most humans for life. Acyclovir is the best drug for therapy to inhibit viral replication now, but drug-resistant [thymidine kinase negative (TK-)]mutants are reported frequently in the clinic. Interferons (IFNs), including IFN- , IFN- and IFN- , are potent antiviral cytokines.Based on the previous study, combination of IFN- and IFN- has the best efficacy to inhibit the replication of wild type virus.In this study, we tested this combination on TK- mutants in vitro using Vero cells and found that IFN- + IFN- reduced the plaque formation of TK-mutants by 50-folds,which they are resistant to acyclovir. In vivo, we infected mice with 2×106 PFU of TK- mutant virus (294dltk) by corneally inoculation, which can result in the reactivation of 294dltk under this condition.
The pretreatment of IFN- and IFN- reduced the viral replication in eyes about 1000-folds on day 1 post infection (p.i.) during acute phase and the ratio of viral reactivation in trigeminal ganglia from 70% to 0% at day 30 p.i. during latent phase. The posttreatment of IFNs also had the same effect but was not effective as pretreatment.
In addition, we tested this on tkLTRZ1 TK- mutant, which reactivates when co-infects with wild type virus. We found that the viral replication in eyes at day 1 p.i. and in ganglia at day 3 p.i. and the viral　reactivation form ganglia, spinal cord and brain stem were reduced after treatment. In order to mimic the immunocompromiced hosts, we used 294dltk to infect ICR-nu mice.Then we compared the viral growth in eyes and ganglia. The preliminary evidence showed that IFNs are able to efficiently inhibit viral growth in immunocompromised hosts. These data suggest that combination of IFN- and IFN- may be an alternative therapy for drug-resistant herpes simplex virus type 1.

INTRODUCTION……………………………………1
MATERIALS AND METHODS………………………5
RESULTS………………………………………………9
DISCUSSION…………………………………………13
REFERENCES…………………………………………16
TABLES………………………………………………20
FIGURES………………………………………………25
APPENDIX……………………………………………27

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