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系統識別號 U0026-2008201214104300
論文名稱(中文) 研究第一型單純疱疹病毒Thymidine kinase突變株在T淋巴細胞缺乏小鼠之復發並測試干擾素對其治療效果
論文名稱(英文) Investigating on the Reactivation and the Interferon Treatment for Thymidine Kinase-Negative Herpes Simplex Virus Type 1 in T-Lymphocyte-Deficient Mice
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 100
學期 2
出版年 101
研究生(中文) 黃文彥
研究生(英文) Wen-Yen Huang
學號 s58931332
學位類別 博士
語文別 英文
論文頁數 75頁
口試委員 指導教授-陳舜華
召集委員-許桂森
召集委員-黃朝慶
召集委員-王憲威
口試委員-徐維莉
口試委員-顧家綺
中文關鍵字 第一型單純疱疹病毒  抗藥性突變株  復發  干擾素 
英文關鍵字 HSV-1  drug-resistant mutants  reactivation  IFN 
學科別分類
中文摘要 由Thymidine kinase (TK) 基因突變,對Acyclovir (ACV) 具有抗藥性的第一型單純疱疹病毒 (HSV-1) 經常從免疫不全的病人復發。然而,由實驗室發展出的TK缺失突變株,並不能從免疫正常的小鼠復發。HSV-1從免疫缺乏的宿主復發,是否需要TK的活性,仍然不清楚。此外,具ACV抗藥性的HSV-1,在免疫缺乏病人身上,造成許多包含腦炎等疾病,因此需要去尋找新的治療方式。在本篇研究中,我們使用由實驗室發展出的TK缺失突變株與免疫缺乏小鼠,探討抗ACV抗藥性TK缺失突變株HSV-1是否能復發。利用ex vivo與in vivo復發模式的結果顯示,TK缺失突變株能由在潛伏感染期,從缺乏CD4與CD8 T細胞小鼠的三叉神經中復發出來,但並不能從野生型小鼠復發。因此,是宿主的免疫反應,而非缺失了TK活性,去抑制HSV-1的復發。雖然CD4和CD8 T細胞在潛伏期感染的小鼠三叉神經中所扮演的角色,已經被描述與研究,但是關於這些T細胞,特別在是TK缺失突變株感染後,在潛伏感染的小鼠腦中調控功能的所知,是非常少的。在本篇第二部份的研究中,我們因此用抗ACV抗藥性TK缺失突變HSV-1去感染野生型小鼠、裸鼠以及Cd4或Cd8基因剔除小鼠。實驗結果顯示,當小鼠缺乏CD4或CD8 T細胞會使得病毒在小鼠腦中,病毒基因潛伏含量增加,並且導致病毒復發。當小鼠同時缺乏CD4及CD8 T細胞時,病毒復發情形則呈現加成效果。因此,CD4與CD8 T細胞是共同合作來調控HSV-1在小鼠腦中的潛伏感染。干擾素(IFN)在臨床上,被用來治療許多其他病毒的感染,並且IFN-和IFN-已經知道可以共同作用去降低HSV-1在免疫正常小鼠的眼角膜複製情形。由於IFN-已知的抗病毒效果是大多是藉由調節T細胞,組合式IFN治療,尤其在免疫不全的宿主,是否依然能抑制抗ACV抗藥性HSV-1病毒複製還未明瞭。在本篇研究的第三部分,我們就去評估組合式IFN治療去對抗抗藥性HSV-1突變株的抑制效果。In vitro的結果顯示,IFN-協同IFN-作用抑制抗藥性HSV-1的複製情形。In vivo結果顯示,從老鼠眼角膜給予組合IFN-和IFN-治療,能有效降野生型小鼠以及免疫不全的裸鼠的眼睛、三叉神經以及腦幹中病毒量,代表這是不透過T細胞的作用。隨後,病毒從三叉神經、腦幹以及脊髓復發的比例也顯著地被降低。因此,組合IFN-和IFN-是為治療在免疫不全的病人身上的抗ACV抗藥性HSV-1感染的一種可行方式。總結而言,我們的研究對於HSV-1在神經系統潛伏感染的免疫調控,有更進一步的認識,並且提供另一種對抗抗藥性HSV-1的治療方式。
英文摘要 Herpes simplex virus type 1 (HSV-1) resistant to antiviral drug, acyclovir (ACV), due to mutations in viral thymidine kinase (tk) gene, which frequently reactivates in immunocompromised patients. However, laboratory strain-derived TK-negative mutants fail to reactivate in immunocompetent mice. Whether TK activity is required for HSV-1 to reactivate in immunocompromised hosts remains unclear. Moreover, ACV-resistant HSV-1 causes severe diseases, including encephalitis, in immunocompromised patients, so identification of new therapies is needed. In this study, we used a laboratory strain-derived TK-negative mutant and immunodeficient mice to investigate whether ACV-resistant, TK-negative HSV-1 could reactivate. Ex vivo and in vivo results showed that such TK-negative mutant reactivated from latently infected trigeminal ganglia of mice deficient in both CD4 and CD8 T cells, but not from wild-type mice. Thus, host immune response, not absence of viral TK activity, blocks HSV-1 reactivation. While the roles of CD4 and CD8 T cells in latently mouse trigeminal ganglia are characterized and investigated, less is known about the regulation of T cells on the latent infection of HSV-1, especially TK-negative mutants, in the mouse brains. In the second part of this study, we therefore infected the wild-type mice, nude mice, Cd4 gene knock-out mice, and Cd8 gene knock-out mice with ACV-resistant, TK-negative HSV-1. Our results show that deficiency of CD4 or CD8 T cells increased the viral genomes and permitted viral reactivation from the latently infected mouse brain. Deficiency of both CD4 and CD8 T cells posed an additive effect in viral reactivation. Hence, CD4 and CD8 T cells collaboratively regulate HSV-1 latency in the mouse brain. Interferons (IFNs) are used to treat several other viral infections in the clinic, and IFN- and IFN- are known to cooperatively reduce wild-type HSV-1 replication in the cornea of immunocompetent mice. Because IFN- has been shown to exert the antiviral effect mostly through T cells, whether combined IFN treatment can still inhibit ACV-resistant HSV-1 replication, especially in immunocompromised hosts, is unknown. In the third part of this study, we evaluated the efficacy of combined IFN treatment on ACV-resistant HSV-1 mutants. In vitro results showed that IFN- acted synergistically with IFN- to inhibit the replication of ACV-resistant HSV-1. In vivo results showed that topical treatment with combined IFN- and IFN- on mouse corneas efficiently reduced the viral loads in the eyes, trigeminal ganglia, and brain stems of wild-type and also immunocompromised nude mice, in a manner independent of T cells. Subsequently, viral reactivation from trigeminal ganglia, brain stems, and spinal cords of mice was significantly inhibited. Thus, a combination of IFN- and IFN- could be a potential treatment for ACV-resistant HSV-1 in immunocompromised patients. Taken together, our study gains a better understanding of the immune regulation in nervous systems during HSV-1 latency and provides an alternative therapy against ACV-resistant mutants.
論文目次 Qualified certificate i
Chinese abstract ii
Abstract iv
Acknowledgements vi
Contents vii
Table list ix
Figure list x
Abbreviations xii
Introduction 1
HSV-1 structure and replication process 1
HSV-1 pathogenesis 2
Anti-HSV-1 treatment and drug resistance 3
Host immune responses in HSV-1 latent infection 7
Interferon treatment 8
Specific aims 10
Materials and methods 13
Cells, viruses, and IFNs 13
Infection of mice treatment of mice with IFN or antibodies to T cells, and tissue collection 13
Flow cytometry analysis 15
Quantitative real-time PCR 16
Assays of HSV-1 reactivation from latently infected mouse TG and brain stems 16
X-gal test and plaque autoradiography 17
Southern blot analysis 18
Plaque reduction and virus replication assays 18
Western blot analysis 18
Statistical analysis 19
Results 20
(1) To examine the reactivation of TK-negative, drug-resistant HSV-1 from T-cell deficient mice 20
(2) To study how T cells regulate HSV-1 latent infection in the mouse CNS 24
(3) To evaluate the antiviral efficacy of combined IFN-β and IFN-γ treatment against drug-resistant HSV-1 in vitro and in vivo, especially in T-cell-deficient mice 29
Discussion 35
Conclusion 43
References 44
Tables 53
Figures 56
Curriculum Vitae 74
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