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。

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.

Adler, H., J. L. Beland, N. C. Del-Pan, L. Kobzik, R. A. Sobel and I. J. Rimm. 1999. In the absence of T cells, natural killer cells protect from mortality due to HSV-1 encephalitis. J Neuroimmunol 93: 208-213.
Al-khatib, K., B. R. Williams, R. H. Silverman, W. Halford and D. J. Carr. 2003. The murine double-stranded RNA-dependent protein kinase PKR and the murine 2',5'-oligoadenylate synthetase-dependent RNase L are required for IFN-beta-mediated resistance against herpes simplex virus type 1 in primary trigeminal ganglion culture. Virology 313: 126-135.
Al-Khatib, K., B. R. Williams, R. H. Silverman, W. Halford and D. J. Carr. 2004. Distinctive roles for 2',5'-oligoadenylate synthetases and double-stranded RNA-dependent protein kinase R in the in vivo antiviral effect of an adenoviral vector expressing murine IFN-beta. J Immunol 172: 5638-5647.
Baringer, J. R. and P. Pisani. 1994. Herpes simplex virus genomes in human nervous system tissue analyzed by polymerase chain reaction. Ann Neurol 36: 823-829.
Beffert, U., P. Bertrand, D. Champagne, S. Gauthier and J. Poirier. 1998. HSV-1 in brain and risk of Alzheimer's disease. Lancet 351: 1330-1331.
Binstock, T. 2001. Anterior insular cortex: linking intestinal pathology and brain function in autism-spectrum subgroups. Med Hypotheses 57: 714-717.
Biron, C. A., K. S. Byron and J. L. Sullivan. 1989. Severe herpesvirus infections in an adolescent without natural killer cells. N Engl J Med 320: 1731-1735.
Biron, C. A., K. B. Nguyen, G. C. Pien, L. P. Cousens and T. P. Salazar-Mather. 1999. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol 17: 189-220.
Cantell, K. 1995. Development of antiviral therapy with alpha interferons: promises, false hopes and accomplishments. Ann Med 27: 23-28.
Cantin, E., B. Tanamachi and H. Openshaw. 1999a. Role for gamma interferon in control of herpes simplex virus type 1 reactivation. J Virol 73: 3418-3423.
Cantin, E., B. Tanamachi, H. Openshaw, J. Mann and K. Clarke. 1999b. Gamma interferon (IFN-gamma) receptor null-mutant mice are more susceptible to herpes simplex virus type 1 infection than IFN-gamma ligand null-mutant mice. J Virol 73: 5196-5200.
Cantin, E. M., D. R. Hinton, J. Chen and H. Openshaw. 1995. Gamma interferon expression during acute and latent nervous system infection by herpes simplex virus type 1. J Virol 69: 4898-4905.
Carr, D. J., K. Al-khatib, C. M. James and R. Silverman. 2003. Interferon-beta suppresses herpes simplex virus type 1 replication in trigeminal ganglion cells through an RNase L-dependent pathway. J Neuroimmunol 141: 40-46.
Cheeseman, S. H., R. H. Rubin, J. A. Stewart, N. E. Tolkoff-Rubin, A. B. Cosimi, K. Cantell, J. Gilbert, S. Winkle, J. T. Herrin, P. H. Black, P. S. Russell and M. S. Hirsch. 1979. Controlled clinical trial of prophylactic human-leukocyte interferon in renal transplantation. Effects on cytomegalovirus and herpes simplex virus infections. N Engl J Med 300: 1345-1349.
Chen, S. H., W. J. Cook, K. L. Grove and D. M. Coen. 1998. Human thymidine kinase can functionally replace herpes simplex virus type 1 thymidine kinase for viral replication in mouse sensory ganglia and reactivation from latency upon explant. J Virol 72: 6710-6715.
Chen, S. H., Y. W. Lin, A. Griffiths, W. Y. Huang and S. H. Chen. 2006a. Competition and complementation between thymidine kinase-negative and wild-type herpes simplex virus during co-infection of mouse trigeminal ganglia. J Gen Virol 87: 3495-3502.
Chen, S. H., A. Pearson and D. M. Coen. 2004. Failure of thymidine kinase-negative herpes simplex virus to reactivate from latency following efficient establishment. J Virol 78: 520-523.
Chen, S. H., H. W. Yao, W. Y. Huang, K. S. Hsu, H. Y. Lei, A. L. Shiau and S. H. Chen. 2006b. Efficient reactivation of latent herpes simplex virus from mouse central nervous system tissues. J Virol 80: 12387-12392.
Cheng, H., T. M. Tumpey, H. F. Staats, N. van Rooijen, J. E. Oakes and R. N. Lausch. 2000. Role of macrophages in restricting herpes simplex virus type 1 growth after ocular infection. Invest Ophthalmol Vis Sci 41: 1402-1409.
Chou, J., J. J. Chen, M. Gross and B. Roizman. 1995. Association of a M(r) 90,000 phosphoprotein with protein kinase PKR in cells exhibiting enhanced phosphorylation of translation initiation factor eIF-2 alpha and premature shutoff of protein synthesis after infection with gamma 134.5- mutants of herpes simplex virus 1. Proc Natl Acad Sci U S A 92: 10516-10520.
Christophers, J., J. Clayton, J. Craske, R. Ward, P. Collins, M. Trowbridge and G. Darby. 1998. Survey of resistance of herpes simplex virus to acyclovir in northwest England. Antimicrob Agents Chemother 42: 868-872.
Coen, D. M., M. Kosz-Vnenchak, J. G. Jacobson, D. A. Leib, C. L. Bogard, P. A. Schaffer, K. L. Tyler and D. M. Knipe. 1989. Thymidine kinase-negative herpes simplex virus mutants establish latency in mouse trigeminal ganglia but do not reactivate. Proc Natl Acad Sci U S A 86: 4736-4740.
Coen, D. M. and P. A. Schaffer. 1980. Two distinct loci confer resistance to acycloguanosine in herpes simplex virus type 1. Proc Natl Acad Sci U S A 77: 2265-2269.
Coen, D. M. and P. A. Schaffer. 2003. Antiherpesvirus drugs: a promising spectrum of new drugs and drug targets. Nat Rev Drug Discov 2: 278-288.
Collins, P. and M. N. Ellis. 1993. Sensitivity monitoring of clinical isolates of herpes simplex virus to acyclovir. J Med Virol Suppl 1: 58-66.
Davar, G., M. F. Kramer, D. Garber, A. L. Roca, J. K. Andersen, W. Bebrin, D. M. Coen, M. Kosz-Vnenchak, D. M. Knipe, X. O. Breakefield and et al. 1994. Comparative efficacy of expression of genes delivered to mouse sensory neurons with herpes virus vectors. J Comp Neurol 339: 3-11.
Decman, V., P. R. Kinchington, S. A. Harvey and R. L. Hendricks. 2005. Gamma interferon can block herpes simplex virus type 1 reactivation from latency, even in the presence of late gene expression. J Virol 79: 10339-10347.
Earnshaw, D. L., T. H. Bacon, S. J. Darlison, K. Edmonds, R. M. Perkins and R. A. Vere Hodge. 1992. Mode of antiviral action of penciclovir in MRC-5 cells infected with herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus. Antimicrob Agents Chemother 36: 2747-2757.
Efstathiou, S., A. C. Minson, H. J. Field, J. R. Anderson and P. Wildy. 1986. Detection of herpes simplex virus-specific DNA sequences in latently infected mice and in humans. J Virol 57: 446-455.
Fleming, H. E., Jr. and D. M. Coen. 1984. Herpes simplex virus mutants resistant to arabinosyladenine in the presence of deoxycoformycin. Antimicrob Agents Chemother 26: 382-387.
Frank, G. M., A. J. Lepisto, M. L. Freeman, B. S. Sheridan, T. L. Cherpes and R. L. Hendricks. 2010. Early CD4(+) T cell help prevents partial CD8(+) T cell exhaustion and promotes maintenance of Herpes Simplex Virus 1 latency. J Immunol 184: 277-286.
Fraser, N. W., W. C. Lawrence, Z. Wroblewska, D. H. Gilden and H. Koprowski. 1981. Herpes simplex type 1 DNA in human brain tissue. Proc Natl Acad Sci U S A 78: 6461-6465.
Gannicliffe, A., J. A. Saldanha, R. F. Itzhaki and R. N. Sutton. 1985. Herpes simplex viral DNA in temporal lobe epilepsy. Lancet 1: 214-215.
Ghiasi, H., S. Cai, G. C. Perng, A. B. Nesburn and S. L. Wechsler. 2000. Both CD4+ and CD8+ T cells are involved in protection against HSV-1 induced corneal scarring. Br J Ophthalmol 84: 408-412.
Ghiasi, H., G. Perng, A. B. Nesburn and S. L. Wechsler. 1999. Either a CD4(+)or CD8(+)T cell function is sufficient for clearance of infectious virus from trigeminal ganglia and establishment of herpes simplex virus type 1 latency in mice. Microb Pathog 27: 387-394.
Griffiths, A., S. H. Chen, B. C. Horsburgh and D. M. Coen. 2003. Translational compensation of a frameshift mutation affecting herpes simplex virus thymidine kinase is sufficient to permit reactivation from latency. J Virol 77: 4703-4709.
Grunewald, K., P. Desai, D. C. Winkler, J. B. Heymann, D. M. Belnap, W. Baumeister and A. C. Steven. 2003. Three-dimensional structure of herpes simplex virus from cryo-electron tomography. Science 302: 1396-1398.
Harle, P., B. Sainz, Jr., D. J. Carr and W. P. Halford. 2002. The immediate-early protein, ICP0, is essential for the resistance of herpes simplex virus to interferon-alpha/beta. Virology 293: 295-304.
Hemling, N., M. Roytta, J. Rinne, P. Pollanen, E. Broberg, V. Tapio, T. Vahlberg and V. Hukkanen. 2003. Herpesviruses in brains in Alzheimer's and Parkinson's diseases. Ann Neurol 54: 267-271.
Horsburgh, B. C., S. H. Chen, A. Hu, G. B. Mulamba, W. H. Burns and D. M. Coen. 1998. Recurrent acyclovir-resistant herpes simplex in an immunocompromised patient: can strain differences compensate for loss of thymidine kinase in pathogenesis? J Infect Dis 178: 618-625.
Itzhaki, R. F., W. R. Lin, D. Shang, G. K. Wilcock, B. Faragher and G. A. Jamieson. 1997. Herpes simplex virus type 1 in brain and risk of Alzheimer's disease. Lancet 349: 241-244.
Jacobson, J. G., S. H. Chen, W. J. Cook, M. F. Kramer and D. M. Coen. 1998. Importance of the herpes simplex virus UL24 gene for productive ganglionic infection in mice. Virology 242: 161-169.
Johnson, A. J., C. F. Chu and G. N. Milligan. 2008. Effector CD4+ T-cell involvement in clearance of infectious herpes simplex virus type 1 from sensory ganglia and spinal cords. J Virol 82: 9678-9688.
Jones, C., M. Inman, W. Peng, G. Henderson, A. Doster, G. C. Perng and A. K. Angeletti. 2005. The herpes simplex virus type 1 locus that encodes the latency-associated transcript enhances the frequency of encephalitis in male BALB/c mice. J Virol 79: 14465-14469.
Kassim, S. H., N. K. Rajasagi, X. Zhao, R. Chervenak and S. R. Jennings. 2006. In vivo ablation of CD11c-positive dendritic cells increases susceptibility to herpes simplex virus type 1 infection and diminishes NK and T-cell responses. J Virol 80: 3985-3993.
Khanna, K. M., A. J. Lepisto, V. Decman and R. L. Hendricks. 2004. Immune control of herpes simplex virus during latency. Curr Opin Immunol 16: 463-469.
Kimberlin, D. W., C. Y. Lin, R. F. Jacobs, D. A. Powell, L. Corey, W. C. Gruber, M. Rathore, J. S. Bradley, P. S. Diaz, M. Kumar, A. M. Arvin, K. Gutierrez, M. Shelton, L. B. Weiner, J. W. Sleasman, T. M. de Sierra, S. Weller, S. J. Soong, J. Kiell, F. D. Lakeman and R. J. Whitley. 2001. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics 108: 230-238.
Knickelbein, J. E., K. M. Khanna, M. B. Yee, C. J. Baty, P. R. Kinchington and R. L. Hendricks. 2008. Noncytotoxic lytic granule-mediated CD8+ T cell inhibition of HSV-1 reactivation from neuronal latency. Science 322: 268-271.
Kodukula, P., T. Liu, N. V. Rooijen, M. J. Jager and R. L. Hendricks. 1999. Macrophage control of herpes simplex virus type 1 replication in the peripheral nervous system. J Immunol 162: 2895-2905.
Kramer, M. F., S. H. Chen, D. M. Knipe and D. M. Coen. 1998. Accumulation of viral transcripts and DNA during establishment of latency by herpes simplex virus. J Virol 72: 1177-1185.
Kramer, M. F. and D. M. Coen. 1995. Quantification of transcripts from the ICP4 and thymidine kinase genes in mouse ganglia latently infected with herpes simplex virus. J Virol 69: 1389-1399.
Larkin, J., L. Jin, M. Farmen, D. Venable, Y. Huang, S. L. Tan and J. I. Glass. 2003. Synergistic antiviral activity of human interferon combinations in the hepatitis C virus replicon system. J Interferon Cytokine Res 23: 247-257.
Le Bon, A. and D. F. Tough. 2002. Links between innate and adaptive immunity via type I interferon. Curr Opin Immunol 14: 432-436.
Lin, Y. W., K. C. Chang, C. M. Kao, S. P. Chang, Y. Y. Tung and S. H. Chen. 2009. Lymphocyte and antibody responses reduce enterovirus 71 lethality in mice by decreasing tissue viral loads. J Virol 83: 6477-6483.
Liu, T., K. M. Khanna, B. N. Carriere and R. L. Hendricks. 2001. Gamma interferon can prevent herpes simplex virus type 1 reactivation from latency in sensory neurons. J Virol 75: 11178-11184.
Liu, T., K. M. Khanna, X. Chen, D. J. Fink and R. L. Hendricks. 2000. CD8(+) T cells can block herpes simplex virus type 1 (HSV-1) reactivation from latency in sensory neurons. J Exp Med 191: 1459-1466.
Liu, T., Q. Tang and R. L. Hendricks. 1996. Inflammatory infiltration of the trigeminal ganglion after herpes simplex virus type 1 corneal infection. J Virol 70: 264-271.
Manickan, E. and B. T. Rouse. 1995. Roles of different T-cell subsets in control of herpes simplex virus infection determined by using T-cell-deficient mouse-models. J Virol 69: 8178-8179.
Martin, J. R. 1981. Herpes simplex virus types 1 and 2 and multiple sclerosis. Lancet 2: 777-781.
Martuza, R. L., A. Malick, J. M. Markert, K. L. Ruffner and D. M. Coen. 1991. Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science 252: 854-856.
Mossman, K. L. and A. A. Ashkar. 2005. Herpesviruses and the innate immune response. Viral Immunol 18: 267-281.
Mossman, K. L., H. A. Saffran and J. R. Smiley. 2000. Herpes simplex virus ICP0 mutants are hypersensitive to interferon. J Virol 74: 2052-2056.
Oberg, B. 1989. Antiviral effects of phosphonoformate (PFA, foscarnet sodium). Pharmacol Ther 40: 213-285.
Pazin, G. J., J. A. Armstrong, M. T. Lam, G. C. Tarr, P. J. Jannetta and M. Ho. 1979. Prevention of reactivated herpes simplex infection by human leukocyte interferon after operation on the trigeminal root. N Engl J Med 301: 225-230.
Pearson, A. and D. M. Coen. 2002. Identification, localization, and regulation of expression of the UL24 protein of herpes simplex virus type 1. J Virol 76: 10821-10828.
Pelosi, E., F. Rozenberg, D. M. Coen and K. L. Tyler. 1998. A herpes simplex virus DNA polymerase mutation that specifically attenuates neurovirulence in mice. Virology 252: 364-372.
Peng, T., J. Zhu, Y. Hwangbo, L. Corey and R. E. Bumgarner. 2008. Independent and cooperative antiviral actions of beta interferon and gamma interferon against herpes simplex virus replication in primary human fibroblasts. J Virol 82: 1934-1945.
Piret, J. and G. Boivin. 2011. Resistance of herpes simplex viruses to nucleoside analogues: mechanisms, prevalence, and management. Antimicrob Agents Chemother 55: 459-472.
Pottage, J. C., Jr. and H. A. Kessler. 1995. Herpes simplex virus resistance to acyclovir: clinical relevance. Infect Agents Dis 4: 115-124.
Roizman, B., D. M. Knipe and R. J. Whitley. 2007. Herpes Simplex Viruses, p. 2501-2601. In D. M. Knipe, P. M. Howley, D. E. Griffin, R. A. Lamb, S. E. Straus, M. A. Martin and B. Roizman (ed.), Fields Virology, 5th ed, vol. 2, Lippincott Williams & Wilkins, Philadelphia, PA.
Saijo, M., T. Suzutani, S. Morikawa and I. Kurane. 2005. Genotypic characterization of the DNA polymerase and sensitivity to antiviral compounds of foscarnet-resistant herpes simplex virus type 1 (HSV-1) derived from a foscarnet-sensitive HSV-1 strain. Antimicrob Agents Chemother 49: 606-611.
Sainz, B., Jr. and W. P. Halford. 2002. Alpha/Beta interferon and gamma interferon synergize to inhibit the replication of herpes simplex virus type 1. J Virol 76: 11541-11550.
Sainz, B., Jr., H. L. LaMarca, R. F. Garry and C. A. Morris. 2005. Synergistic inhibition of human cytomegalovirus replication by interferon-alpha/beta and interferon-gamma. Virol J 2: 14.
Sainz, B., Jr., E. C. Mossel, C. J. Peters and R. F. Garry. 2004. Interferon-beta and interferon-gamma synergistically inhibit the replication of severe acute respiratory syndrome-associated coronavirus (SARS-CoV). Virology 329: 11-17.
Sanchez-Carpintero, R., S. Aguilera, M. Idoate and B. Bejarano. 2008. Temporal lobectomy in acute complicated herpes simplex encephalitis: technical case report. Neurosurgery 62: E1174-1175; discussion E1175.
Sawtell, N. M. and R. L. Thompson. 1992. Rapid in vivo reactivation of herpes simplex virus in latently infected murine ganglionic neurons after transient hyperthermia. J Virol 66: 2150-2156.
Schnipper, L. E. and C. S. Crumpacker. 1980. Resistance of herpes simplex virus to acycloguanosine: role of viral thymidine kinase and DNA polymerase loci. Proc Natl Acad Sci U S A 77: 2270-2273.
Schoenborn, J. R. and C. B. Wilson. 2007. Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol 96: 41-101.
Sciammas, R., P. Kodukula, Q. Tang, R. L. Hendricks and J. A. Bluestone. 1997. T cell receptor-gamma/delta cells protect mice from herpes simplex virus type 1-induced lethal encephalitis. J Exp Med 185: 1969-1975.
Segre, J. A., J. L. Nemhauser, B. A. Taylor, J. H. Nadeau and E. S. Lander. 1995. Positional cloning of the nude locus: genetic, physical, and transcription maps of the region and mutations in the mouse and rat. Genomics 28: 549-559.
Sekizawa, T. and H. Openshaw. 1984. Encephalitis resulting from reactivation of latent herpes simplex virus in mice. J Virol 50: 263-266.
Staats, H. F., J. E. Oakes and R. N. Lausch. 1991. Anti-glycoprotein D monoclonal antibody protects against herpes simplex virus type 1-induced diseases in mice functionally depleted of selected T-cell subsets or asialo GM1+ cells. J Virol 65: 6008-6014.
Stranska, R., R. Schuurman, E. Nienhuis, I. W. Goedegebuure, M. Polman, J. F. Weel, P. M. Wertheim-Van Dillen, R. J. Berkhout and A. M. van Loon. 2005. Survey of acyclovir-resistant herpes simplex virus in the Netherlands: prevalence and characterization. J Clin Virol 32: 7-18.
Stranska, R., A. M. van Loon, M. Polman, M. F. Beersma, R. G. Bredius, A. C. Lankester, E. Meijer and R. Schuurman. 2004. Genotypic and phenotypic characterization of acyclovir-resistant herpes simplex viruses isolated from haematopoietic stem cell transplant recipients. Antivir Ther 9: 565-575.
Tenser, R. B. and W. A. Edris. 1987. Trigeminal ganglion infection by thymidine kinase-negative mutants of herpes simplex virus after in vivo complementation. J Virol 61: 2171-2174.
Tenser, R. B., A. Gaydos and K. A. Hay. 1996. Reactivation of thymidine kinase-defective herpes simplex virus is enhanced by nucleoside. J Virol 70: 1271-1276.
Tenser, R. B., R. L. Miller and F. Rapp. 1979. Trigeminal ganglion infection by thymidine kinase-negative mutants of herpes simplex virus. Science 205: 915-917.
Valyi-Nagy, T., R. M. Gesser, B. Raengsakulrach, S. L. Deshmane, B. P. Randazzo, A. J. Dillner and N. W. Fraser. 1994. A thymidine kinase-negative HSV-1 strain establishes a persistent infection in SCID mice that features uncontrolled peripheral replication but only marginal nervous system involvement. Virology 199: 484-490.
Virelizier, J. L. and F. Arenzana-Seisdedos. 1985. Immunological functions of macrophages and their regulation by interferons. Med Biol 63: 149-159.
Wang, K., G. Mahalingam, S. E. Hoover, E. K. Mont, S. M. Holland, J. I. Cohen and S. E. Straus. 2007. Diverse herpes simplex virus type 1 thymidine kinase mutants in individual human neurons and Ganglia. J Virol 81: 6817-6826.
Wentworth, B. B. and E. R. Alexander. 1971. Seroepidemiology of infectious due to members of the herpesvirus group. Am J Epidemiol 94: 496-507.
Whitley, R. J. 1991. Herpes simplex virus infections of the central nervous system. Encephalitis and neonatal herpes. Drugs 42: 406-427.
Whitley, R. J. 2002. Herpes simplex virus infection. Semin Pediatr Infect Dis 13: 6-11.
Whitley, R. J. and B. Roizman. 2001. Herpes simplex virus infections. Lancet 357: 1513-1518.