根據血清學的調查結果發現，全世界的成年人口中有百分之九十曾經受到單純疱疹病毒第一型的感染。　　另外，利用PCR的方式而在高達百分之八十的癲癇或多發性硬化症患者腦部的檢體可發現有單純疱疹病毒的DNA存在，此比例遠高於沒有神經性疾病的族群(約34-50%)。　　除此之外，單純疱疹病毒在腦部的潛伏性感染可能與老人癡呆症也就是阿茲海默症的發展有關。　　然而，在廣大的感染族群中，只有部分的人會遭遇病毒在腦部產生復發進而造成神經性疾病。　　因此，釐清究竟是哪些因子決定病毒是否在腦部產生復發成為一個探討單純疱疹病毒與腦部神經性疾病之間關係的重要課題。　　在本篇研究中，我們利用四種不同的病毒株，分別為KOS、RE、294.1和McKrae，以及三種不同品系的老鼠，分別為ICR、BALB/c和C57BL/6來探討病毒毒力及宿主的耐受性是否會影響病毒在腦部復發的比例和機制。　　我們觀察到具有高毒性的病毒株，如294.1和McKrae，較容易在老鼠的腦部發生復發。　　因為，高毒性病毒株可以在老鼠體內有較長的急性感染期並儲存較多的病毒DNA在老鼠的腦組織中。　　而弱毒性病毒株，例如KOS和RE，在感染老鼠後進行的急性感染期較短，建立的潛伏性感染也較差。　　此外，不同品系的老鼠在感染的耐受性、病毒的複製和潛伏期的建立等方面有程度上的差異，進而影響病毒在腦部復發的比例。　　在本篇研究中，我們發現對病毒可以在較敏感的老鼠品系，如ICR和BALB/c，有較高比率的腦部復發，歸因於病毒有良好的急性期複製與潛伏期的建立。　　總結本篇研究，我們發現單純疱疹病毒在腦部的復發會受到病毒毒力以及宿主耐受性差異的影響。　　此結果將提供了日後探討單純疱疹病毒在腦部復發與腦部神經性疾病關聯性的研究基礎。

　Around　34-50%　of　humans　have　herpes　simplex　virus　type　I　(HSV-1)　genomes　in　their　brains,　but　only　a　fraction　of　this　population　experiences　viral　reactivation　in　the　brains.　　Why　some　individuals　experience　viral　reactivation　from　latently　infected　brains　and　how　virus　contributes　to　this　process　need　to　be　clarified.　　In　this　study,　we　systematically　investigated　the　contribution　of　both　viral　and　host　factors　to　HSV-1　reactivation　from　latently　infected　mouse　brain　stems.　　Four　HSV-1　strains　varied　in　their　virulence　were　used　to　study　the　role　of　viral　factor　in　HSV-1　reactivation　from　latently　infected　brain　stems.　　We　observed　that　viral　strains　with　high　virulence,　such　as　294.1　and　McKrae,　replicated　longer　in　the　brain　during　acute　phase,　deposited　more　viral　genomes　in　the　brain　during　latency,　and　subsequently　reactivated　from　latently　infected　mouse　brain　stems　with　higher　frequencies　than　avirulent　strains,　RE　and　KOS.　　Meanwhile,　three　mouse　strains　varied　in　their　susceptibility　to　HSV-1　infection.　　ICR　mice　were　most　susceptible　followed　by　BALB/c　and　then　C57BL/6　mice.　　So　these　three　strains　of　mice　were　used　to　examine　the　role　of　host　factor　in　HSV-1　reactivation　from　latently　infected　brain　stems.　　We　demonstrated　that　the　reactivation　rate　was　correlated　with　the　susceptibilities　of　mouse　strains　to　viral　infection.　　Our　results　indicated　that　both　viral　and　host　factors　influence　the　reactivation　of　HSV-1　from　latently　infected　brains.　　This　study　might　provide　foundation　for　future　studies　on　HSV-1　reactivation　from　the　brain　to　cause　recurrent　infections　in　humans　with　neurological　diseases.

References
1. Roizman, B. & Pellett, P.E. The family herpesviridae: A brief introduction. in Fields Virology, Vol. 2 (eds. Knipe, D.M. et al.) 2381-2398 (Lippincott Williams & Wilkins, Philadelphia, 2001).
2. Roizman, B. & Knipe, D.M. Herpes simplex viruses and their replication. in Fields Virology, Vol. 2 (eds. Knipe, D.M. et al.) 2399-2459 (Lippincott Williams & Wilkins, Philadelphia, 2001).
3. Whitley, R.J. Herpes simplex viruses. in Fields Virology, Vol. 2 (eds. Knipe, D.M. et al.) 2461-2510 (Lippincott Williams & Wilkins, Philadelphia, 2001).
4. Stevens, J.G., Wagner, E.K., Devi-Rao, G.B., Cook, M.L. & Feldman, L.T. RNA complementary to a herpesvirus alpha gene mRNA is prominent in latently infected neurons. Science 235, 1056-9 (1987).
5. Wentworth, B.B. & Alexander, E.R. Seroepidemiology of infectious due to members of the herpesvirus group. Am. J. Epidemiol. 94, 496-507 (1971).
6. Stevens, J.G. & Cook, M.L. Latent herpes simplex virus in spinal ganglia of mice. Science 173, 843-5 (1971).
7. Schmutzhard, E. Viral infections of the CNS with special emphasis on herpes simplex infections. J. Neurol. 248, 469-77 (2001).
8. Fraser, N.W., Lawrence, W.C., Wroblewska, Z., Gilden, D.H. & Koprowski, H. Herpes simplex type 1 DNA in human brain tissue. Proc. Natl. Acad. Sci. U. S. A. 78, 6461-5 (1981).
9. Sanders, V.J. et al. Presence of herpes simplex DNA in surgical tissue from human epileptic seizure foci detected by polymerase chain reaction: preliminary study. Arch. Neurol. 54, 954-60 (1997).
10. Sanders, V.J. et al. Herpes simplex virus in postmortem multiple sclerosis brain tissue. Arch. Neurol. 53, 125-33 (1996).
11. Sanders, V.J., Felisan, S., Waddell, A. & Tourtellotte, W.W. Detection of herpesviridae in postmortem multiple sclerosis brain tissue and controls by polymerase chain reaction. J. Neurovirol. 2, 249-58 (1996).
12. Hemling, N. et al. Herpesviruses in brains in Alzheimer's and Parkinson's diseases. Ann. Neurol. 54, 267-71 (2003).
13. Itzhaki, R. Herpes simplex virus type 1, apolipoprotein E and Alzheimer' disease. Herpes 11 Suppl 2, 77A-82A (2004).
14. Itzhaki, R.F. Possible factors in the etiology of Alzheimer's disease. Mol. Neurobiol. 9, 1-13 (1994).
15. Itzhaki, R.F. et al. Herpes simplex virus type 1 in brain and risk of Alzheimer's disease. Lancet 349, 241-4 (1997).
16. Itzhaki, R.F. & Wozniak, M.A. Alzheimer's disease, the neuroimmune axis, and viral infection. J. Neuroimmunol. 156, 1-2 (2004).
17. Mori, I. et al. Reactivation of HSV-1 in the brain of patients with familial Alzheimer's disease. J. Med. Virol. 73, 605-11 (2004).
18. Abghari, S.Z. & Stulting, R.D. Recovery of herpes simplex virus from ocular tissues of latently infected inbred mice. Invest. Ophthalmol. Vis. Sci. 29, 239-43 (1988).
19. Ellison, A.R., Yang, L., Voytek, C. & Margolis, T.P. Establishment of latent herpes simplex virus type 1 infection in resistant, sensitive, and immunodeficient mouse strains. Virology 268, 17-28 (2000).
20. Perng, G.C., Slanina, S.M., Ghiasi, H., Nesburn, A.B. & Wechsler, S.L. The effect of latency-associated transcript on the herpes simplex virus type 1 latency-reactivation phenotype is mouse strain-dependent. J. Gen. Virol. 82, 1117-22 (2001).
21. Thompson, R.L. & Sawtell, N.M. The herpes simplex virus type 1 latency-associated transcript gene regulates the establishment of latency. J. Virol. 71, 5432-40 (1997).
22. Strelow, L.I. et al. A structural and functional comparison of the latency-associated transcript promoters of herpes simplex virus type 1 strains KOS and McKrae. J. Gen. Virol. 75 ( Pt 9), 2475-80 (1994).
23. Perng, G.C. et al. A herpes simplex virus type 1 latency-associated transcript mutant with increased virulence and reduced spontaneous reactivation. J. Virol. 73, 920-9 (1999).
24. Sawtell, N.M., Poon, D.K., Tansky, C.S. & Thompson, R.L. The latent herpes simplex virus type 1 genome copy number in individual neurons is virus strain specific and correlates with reactivation. J. Virol. 72, 5343-50 (1998).
25. Sawtell, N.M. & Thompson, R.L. Rapid in vivo reactivation of herpes simplex virus in latently infected murine ganglionic neurons after transient hyperthermia. J. Virol. 66, 2150-6 (1992).
26. Hill, J.M., Rayfield, M.A. & Haruta, Y. Strain specificity of spontaneous and adrenergically induced HSV-1 ocular reactivation in latently infected rabbits. Curr. Eye. Res. 6, 91-7 (1987).
27. Cantin, E.M. et al. Expression of herpes simplex virus 1 glycoprotein B by a recombinant vaccinia virus and protection of mice against lethal herpes simplex virus 1 infection. Proc. Natl. Acad. Sci. U. S. A. 84, 5908-12 (1987).
28. Kramer, M.F. & Coen, D.M. Quantification of transcripts from the ICP4 and thymidine kinase genes in mouse ganglia latently infected with herpes simplex virus. J. Virol. 69, 1389-99 (1995).
29. Katz, J.P., Bodin, E.T. & Coen, D.M. Quantitative polymerase chain reaction analysis of herpes simplex virus DNA in ganglia of mice infected with replication-incompetent mutants. J. Virol. 64, 4288-95 (1990).
30. Leib, D.A. et al. Immediate-early regulatory gene mutants define different stages in the establishment and reactivation of herpes simplex virus latency. J. Virol. 63, 759-68 (1989).
31. Sawtell, N.M. & Thompson, R.L. Herpes simplex virus type 1 latency-associated transcription unit promotes anatomical site-dependent establishment and reactivation from latency. J. Virol. 66, 2157-69 (1992).
32. Cai, W. et al. The herpes simplex virus type 1 regulatory protein ICP0 enhances virus replication during acute infection and reactivation from latency. J. Virol. 67, 7501-12 (1993).
33. Izumi, K.M. & Stevens, J.G. Molecular and biological characterization of a herpes simplex virus type 1 (HSV-1) neuroinvasiveness gene. J. Exp. Med. 172, 487-96 (1990).
34. Weise, K., Kaerner, H.C., Glorioso, J. & Schroder, C.H. Replacement of glycoprotein B gene sequences in herpes simplex virus type 1 strain ANG by corresponding sequences of the strain KOS causes changes of plaque morphology and neuropathogenicity. J. Gen. Virol. 68 ( Pt 7), 1909-19 (1987).
35. Campadelli-Fiume, G. et al. Glycoprotein C-dependent attachment of herpes simplex virus to susceptible cells leading to productive infection. Virology 178, 213-22 (1990).
36. Yuhasz, S.A. & Stevens, J.G. Glycoprotein B is a specific determinant of herpes simplex virus type 1 neuroinvasiveness. J. Virol. 67, 5948-54 (1993).
37. Stevens, J.G. HSV-1 neuroinvasiveness. Intervirology 35, 152-63 (1993).
38. Day, S.P., Lausch, R.N. & Oakes, J.E. Nucleotide sequences important in DNA replication are responsible for differences in the capacity of two herpes simplex virus strains to spread from cornea to central nervous system. Curr. Eye Res. 6, 19-26 (1987).
39. Pelosi, E., Rozenberg, F., Coen, D.M. & Tyler, K.L. A herpes simplex virus DNA polymerase mutation that specifically attenuates neurovirulence in mice. Virology 252, 364-72 (1998).
40. O'Neil, J.E. et al. Wide variations in herpes simplex virus type 1 inoculum dose and latency-associated transcript expression phenotype do not alter the establishment of latency in the rabbit eye model. J. Virol. 78, 5038-44 (2004).
41. Cassady, K.A., Gross, M., Gillespie, G.Y. & Roizman, B. Second-site mutation outside of the U(S)10-12 domain of Deltagamma(1)34.5 herpes simplex virus 1 recombinant blocks the shutoff of protein synthesis induced by activated protein kinase R and partially restores neurovirulence. J. Virol. 76, 942-9 (2002).
42. Zhu, J. et al. Identification of a novel 0.7-kb polyadenylated transcript in the LAT promoter region of HSV-1 that is strain specific and may contribute to virulence. Virology 265, 296-307 (1999).
43. Perng, G.C. et al. The latency-associated transcript gene enhances establishment of herpes simplex virus type 1 latency in rabbits. J. Virol. 74, 1885-91 (2000).
44. Perng, G.C. et al. The latency-associated transcript gene of herpes simplex virus type 1 (HSV-1) is required for efficient in vivo spontaneous reactivation of HSV-1 from latency. J. Virol. 68, 8045-55 (1994).
45. Leib, D.A. et al. A deletion mutant of the latency-associated transcript of herpes simplex virus type 1 reactivates from the latent state with reduced frequency. J. Virol. 63, 2893-900 (1989).
46. Lopez, C. Genetics of natural resistance to herpesvirus infections in mice. Nature 258, 152-3 (1975).
47. Scalzo, A.A., Fitzgerald, N.A., Simmons, A., La Vista, A.B. & Shellam, G.R. Cmv-1, a genetic locus that controls murine cytomegalovirus replication in the spleen. J. Exp. Med. 171, 1469-83 (1990).
48. Sarmiento, M. Intrinsic resistance to viral infection. Mouse macrophage restriction of herpes simplex virus replication. J. Immunol. 141, 2740-8 (1988).
49. Lee, S.H. et al. Susceptibility to mouse cytomegalovirus is associated with deletion of an activating natural killer cell receptor of the C-type lectin superfamily. Nat. Genet. 28, 42-5 (2001).
50. Forbes, C.A. et al. The Cmv1 host resistance locus is closely linked to the Ly49 multigene family within the natural killer cell gene complex on mouse chromosome 6. Genomics 41, 406-13 (1997).
51. Lee, S.H. et al. Transgenic expression of the activating natural killer receptor Ly49H confers resistance to cytomegalovirus in genetically susceptible mice. J. Exp. Med. 197, 515-26 (2003).
52. Daniels, K.A. et al. Murine cytomegalovirus is regulated by a discrete subset of natural killer cells reactive with monoclonal antibody to Ly49H. J. Exp. Med. 194, 29-44 (2001).
53. Scalzo, A.A. et al. The effect of the Cmv-1 resistance gene, which is linked to the natural killer cell gene complex, is mediated by natural killer cells. J. Immunol. 149, 581-9 (1992).
54. Zawatzky, R., Gresser, I., DeMaeyer, E. & Kirchner, H. The role of interferon in the resistance of C57BL/6 mice to various doses of herpes simplex virus type 1. J. Infect. Dis. 146, 405-10 (1982).
55. Quinnan, G.V., Jr. & Manischewitz, J.F. Genetically determined resistance to lethal murine cytomegalovirus infection is mediated by interferon-dependent and -independent restriction of virus replication. J. Virol. 61, 1875-81 (1987).
56. Chaudhri, G. et al. Polarized type 1 cytokine response and cell-mediated immunity determine genetic resistance to mousepox. Proc. Natl. Acad. Sci. U. S. A. 101, 9057-62 (2004).
57. Lathbury, L.J., Allan, J.E., Shellam, G.R. & Scalzo, A.A. Effect of host genotype in determining the relative roles of natural killer cells and T cells in mediating protection against murine cytomegalovirus infection. J. Gen. Virol. 77 ( Pt 10), 2605-13 (1996).
58. He, X., Yoshida, H., Minamishima, Y. & Nomoto, K. Analysis of the role of CD4+ T-cells during murine cytomegalovirus infection in different strains of mice. Virus Res. 36, 233-45 (1995).
59. Lundberg, P. et al. A locus on mouse chromosome 6 that determines resistance to herpes simplex virus also influences reactivation, while an unlinked locus augments resistance of female mice. J. Virol. 77, 11661-73 (2003).
60. Mitchell, W.J., De Santo, R.J., Zhang, S.D., Odenwald, W.F. & Arnheiter, H. Herpes simplex virus pathogenesis in transgenic mice is altered by the homeodomain protein Hox 1.3. J. Virol. 67, 4484-91 (1993).
61. Galle, L.E., Taus, N.S., Maggs, D.J., Moore, C.P. & Mitchell, W.J. Increased severity of herpes simplex virus type 1-induced keratitis in Hox A5 transgenic mice. Curr. Eye Res. 23, 435-42 (2001).