Advertisement

Update on Herpes Virus Infections of the Nervous System

  • Israel Steiner
  • Felix Benninger
Infection (J Berger, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Infection

Abstract

Herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2) are human neurotropic viruses that establish latent infection in dorsal root ganglia (DRG) for the entire life of the host. From the DRG they can reactivate to cause human morbidity and mortality. Although they vary, in part, in the clinical disorders they cause, and in their molecular structure, they share several features that govern the biology of their infection of the human nervous system. HSV-1 is the causative agent of encephalitis, corneal blindness, and several peripheral nervous system disorders; HSV-2 is responsible for meningoencephalitis in neonates and meningitis in adults. The biology of their ability to establish latency, maintain it for the entire life of the host, reactivate, and cause primary and recurrent disease is being studied in animal models and in humans. This review covers recent advances in understanding the biology and pathogenesis of HSV-related disease.

Keywords

Herpes virus infections HSV Nervous system HSV-1 HSV-2 Herpes simplex encephalitis HSE 

Notes

Acknowledgment

Felix Benninger received the Beilinson Hospital Young Investigators Grant in 2012.

Compliance with Ethics Guidelines

Conflict of Interest

Israel Steiner serves on the editorial board of the Journal of Neurological Sciences, Journal of Neurovirology, and Medicine Neurology (Hebrew). He is a consultant and member of DSMB for Actelion and Genentech/Roche. He has received honoraria from Teva Pharmaceutical Industries Ltd. He has also received travel/accommodations expenses covered or reimbursed from Beilinson Hospital, Petach Tikva, Israel.

Felix Benninger declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Gilden DH, Mahalingam R, Cohrs RJ, Tyler KL. Herpesvirus infections of the nervous system. Nat Clin Pract Neurol. 2007;3:82–94.PubMedCrossRefGoogle Scholar
  2. 2.
    Dolan A, Jamieson FE, Cunningham C. The genome sequence of herpes simplex virus type 2. J Virol. 1998;72:2010–21.PubMedGoogle Scholar
  3. 3.
    McGeoch DJ, Dolan A, Donald S, Brauer DHK. Complete DNA sequence of the short repeat region in the genome of herpes simplex virus type 1. Nucl Acids Res. 1986;14:1727–45.PubMedCrossRefGoogle Scholar
  4. 4.
    McGeoch DJ. The genomes of the human herpesviruses: contents, relationships, and evolution. Annu Rev Microbiol. 1989;43:235–65.PubMedCrossRefGoogle Scholar
  5. 5.
    • Egan KP, Wu S, Wigdahl B, Jennings SR. Immunological control of herpes simplex virus infections. J Neurovirol. 2013;19:328–45. Comprehensive description of immune mechanisms involved in latency and virus control.PubMedCrossRefGoogle Scholar
  6. 6.
    Kennedy PGE, Chaudhuri A. Herpes simplex encephalitis. J Neurol Neurosurg Psychiatry. 2002;73:237–38.PubMedCrossRefGoogle Scholar
  7. 7.
    Steiner I. Herpes simplex virus meningoencephalitis. In: Jackson AC, editor. Viral infections of the human nervous system. Birkhäuser advances in infectious diseases. Basel: Springer; 2013. pp. 47–63.Google Scholar
  8. 8.
    Abaitua F, Zia R, Hollinshead M, O'Hare P. Polarised cell migration during cell-to-cell transmission of herpes simplex virus in human skin keratinocytes. J Virol. 2013;87:7921–32.PubMedCrossRefGoogle Scholar
  9. 9.
    Lee JI, Sollars PJ, Baver SB, Pickard GE. A herpesvirus encoded deubiquitinase is a novel neuroinvasive determinant. PLoS Pathogens. 2009;5:e1000387.PubMedCrossRefGoogle Scholar
  10. 10.
    Böttcher S, Maresch C, Granzow H, Klupp BG, Teifke JP, Mettenleiter TC. Mutagenesis of the active-site cysteine in the ubiquitin-specific protease contained in large tegument protein pUL36 of pseudorabies virus impairs viral replication in vitro and neuroinvasion in vivo. J Virol. 2008;82:6009–16.PubMedCrossRefGoogle Scholar
  11. 11.
    Antinone SE, Smith GA. Retrograde axon transport of herpes simplex virus and pseudorabies virus: a live-cell comparative analysis. J Virol. 2010;84:1504–12.PubMedCrossRefGoogle Scholar
  12. 12.
    Feierbach B, Bisher M, Goodhouse J, Enquist LW. In Vitro analysis of transneuronal spread of an alphaherpesvirus infection in peripheral nervous system neurons. J Virol. 2007;81:6846–57.PubMedCrossRefGoogle Scholar
  13. 13.
    Granstedt AE, Brunton BW, Enquist LW. (2013) Imaging the transport dynamics of single alphaherpesvirus particles in intact peripheral nervous system explants from infected mice. mBio 4: e00358–13–e00358–13.Google Scholar
  14. 14.
    Bertke AS, Apakupakul K, Ma A, Imai Y, Gussow AM, Wang K, et al. LAT region factors mediating differential neuronal tropism of HSV-1 and HSV-2 do not act in trans. PLoS One. 2012;7:e53281.PubMedCrossRefGoogle Scholar
  15. 15.
    Bloom DC, Kwiatkowski DL. HSV-1 latency and the roles of the LATs. In Weller (ed.) Alphaherpesviruses: molecular virology. Caister Academic Press; 2011, pp. 286–312.Google Scholar
  16. 16.
    Bertke AS, Swanson SM, Chen J, Imai Y, Kinchington PR, Margolis TP. A5-positive primary sensory neurons are nonpermissive for productive infection with herpes simplex virus 1 in vitro. J Virol. 2011;85:6669–77.PubMedCrossRefGoogle Scholar
  17. 17.
    Knipe DM, Cliffe A. Chromatin control of herpes simplex virus lytic and latent infection. Nat Rev Micro. 2008;6:211–21.CrossRefGoogle Scholar
  18. 18.
    Bloom DC, Giordani NV, Kwiatkowski DL. Epigenetic regulation of latent HSV-1 gene expression. Biochim Biophys Acta. 2010;1799:246–56.PubMedCrossRefGoogle Scholar
  19. 19.
    Su Y-H, Moxley MJ, Ng AK, Lin J, Jordan R, Fraser NW, et al. Stability and circularization of herpes simplex virus type 1 genomes in quiescently infected PC12 cultures. J Gen Virol. 2002;83:2943–50.PubMedGoogle Scholar
  20. 20.
    Steiner I, Spivack JG, O'Boyle DR, Lavi E, Fraser NW. Latent herpes simplex virus type 1 transcription in human trigeminal ganglia. J Virol. 1988;62:3493–6.PubMedGoogle Scholar
  21. 21.
    Stevens JG, Wagner EK, Devi-Rao GB, Cook ML, Feldman LT. RNA complementary to a herpesvirus alpha gene mRNA is prominent in latently infected neurons. Science. 1987;235:1056–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Trousdale MD, Steiner I, Spivack JG, Deshmane SL, Brown SM, MacLean AR, et al. In vivo and in vitro reactivation impairment of a herpes simplex virus type 1 latency-associated transcript variant in a rabbit eye model. J Virol. 1991;65:6989–93.PubMedGoogle Scholar
  23. 23.
    Steiner I, Spivack JG, Lirette RP, Brown SM, MacLean AR, Subak-Sharpe JH, et al. Herpes simplex virus type 1 latency-associated transcripts are evidently not essential for latent infection. EMBO J. 1989;8:505–11.PubMedGoogle Scholar
  24. 24.
    Carpenter D, Hsiang C, Brown DJ, Jin L, Osorio N, BenMohamed L, et al. Stable cell lines expressing high levels of the herpes simplex virus type 1 LAT are refractory to caspase 3 activation and DNA laddering following cold shock induced apoptosis. Virology. 2007;369:12–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Branco FJ, Fraser NW. Herpes simplex virus type 1 latency-associated transcript expression protects trigeminal ganglion neurons from apoptosis. J Virol. 2005;79:9019–25.PubMedCrossRefGoogle Scholar
  26. 26.
    Perng G-C, Jones C. Towards an understanding of the herpes simplex virus type 1 latency-reactivation cycle. In Solbrig (ed.) Interdisciplinary perspectives on infectious diseases. Hindawi Publishing Corporation;2010, pp. 1–18. Google Scholar
  27. 27.
    Jurak I, Silverstein LB, Sharma M, Coen DM. Herpes simplex virus is equipped with RNA-and protein-based mechanisms to repress expression of ATRX, an effector of intrinsic immunity. J Virol. 2012;86:10093–102.PubMedCrossRefGoogle Scholar
  28. 28.
    •• Nicoll MP, Proença JT, Efstathiou S. The molecular basis of herpes simplex virus latency. FEMS Microbiol Rev. 2012;36:684–705. Latest experimental research on the control of herpes virus latency in neurons.PubMedCrossRefGoogle Scholar
  29. 29.
    Held K, Derfuss T. Control of HSV-1 latency in human trigeminal ganglia—current overview. J Neurovirol. 2011;17:518–27.PubMedCrossRefGoogle Scholar
  30. 30.
    Goldenberg D, Mador N, Ball MJ, Panet A, Steiner I. The abundant latency-associated transcripts of herpes simplex virus type 1 are bound to polyribosomes in cultured neuronal cells and during latent infection in mouse trigeminal ganglia. J Virol. 1997;71:2897–904.PubMedGoogle Scholar
  31. 31.
    Feldman LT. Spontaneous molecular reactivation of herpes simplex virus type 1 latency in mice. Proc Natl Acad Sci U S A. 2002;99:978–83.PubMedCrossRefGoogle Scholar
  32. 32.
    Wysocka J, Herr W. The herpes simplex virus VP16-induced complex: the makings of a regulatory switch. Trends Biochem Sci. 2003;28:294–304.PubMedCrossRefGoogle Scholar
  33. 33.
    Thompson RL, Preston CM, Sawtell NM. De novo synthesis of VP16 coordinates the exit from HSV latency in vivo. PLoS Pathogens. 2009;5:e1000352.PubMedCrossRefGoogle Scholar
  34. 34.
    Huang J, Lazear HM, Friedman HM. Completely assembled virus particles detected by transmission electron microscopy in proximal and mid-axons of neurons infected with herpes simplex virus type 1, herpes simplex virus type 2 and pseudorabies virus. Virology. 2011;409:12–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Wisner TW, Sugimoto K, Howard PW, Kawaguchi Y, Johnson DC. Anterograde transport of herpes simplex virus capsids in neurons by both separate and married mechanisms. J Virol. 2011;85:5919–28.PubMedCrossRefGoogle Scholar
  36. 36.
    Karasneh GA, Shukla D. Herpes simplex virus infects most cell types in vitro: clues to its success. Virol J. 2011;8:481.PubMedCrossRefGoogle Scholar
  37. 37.
    Kaye S, Choudhary A. Herpes simplex keratitis. Prog Retin Eye Res. 2006;25:355–80.PubMedCrossRefGoogle Scholar
  38. 38.
    • Steiner I. Herpes simplex virus encephalitis: new infection or reactivation? Curr Opin Neurol. 2011;24:268–74. Discussion about the etiology of herpes encephalitis and if to consider a primary injection or reactivation.PubMedCrossRefGoogle Scholar
  39. 39.
    Solomon T, Michael B, Smith P, Sanderson F. Management of suspected viral encephalitis in adults–Association of British Neurologists and British Infection Association National Guidelines. J Infect. 2012;64:347–73.PubMedCrossRefGoogle Scholar
  40. 40.
    Whitley RJ, Alford CA, Hirsch MS, Schooley RT, Luby JP, Aoki FY, et al. Vidarabine versus acyclovir therapy in herpes simplex encephalitis. N Engl J Med. 1986;314:144–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Whitley RJ. Viral encephalitis. N Engl J Med. 1990;323:242–50.PubMedCrossRefGoogle Scholar
  42. 42.
    Kennedy PGE, Steiner I. Recent issues in herpes simplex encephalitis. J Neurovirol. 2013;19:346–50.PubMedCrossRefGoogle Scholar
  43. 43.
    Landau Z, Miller E, Roif M. Recurrent herpes simplex encephalitis. Eur J Int Med. 2005;16:513–14.CrossRefGoogle Scholar
  44. 44.
    Yamada S, Kameyama T, Nagaya S, Hashizume Y, Yoshida M. Relapsing herpes simplex encephalitis: pathological confirmation of viral reactivation. J Neurol Neurosurg Psychiatry. 2003;74:262–4.PubMedCrossRefGoogle Scholar
  45. 45.
    Whitley RJ. Herpes simplex virus. In: Sheld, Whitley, and Marra (eds.) Infections of the central nervous system. Lippincott Williams & Wilkins; 2004, pp. 123–44.Google Scholar
  46. 46.
    Whitley RJ. Herpes simplex encephalitis clinical assessment. JAMA. 1982;247:317–20.PubMedCrossRefGoogle Scholar
  47. 47.
    Baskin HJ, Hedlund G. Neuroimaging of herpesvirus infections in children. Pediatr Radiol. 2007;37:949–63.PubMedCrossRefGoogle Scholar
  48. 48.
    Castillo M, Rumboldt Z. Herpes simplex encephalitis. In Rumboldt et al. (ed.) Brain imaging with MRI and CT: an image pattern approach. Cambridge University Press, New York 2012, pp. 41–2Google Scholar
  49. 49.
    Esiri MM. Herpes simplex encephalitis: an immunohistological study of the distribution of viral antigen within the brain. J Neurol Sci. 1982;54:209–26.PubMedCrossRefGoogle Scholar
  50. 50.
    Tissari J, Sirén J, Meri S, Julkunen I, Matikainen S. IFN-α enhances TLR3-mediated antiviral cytokine expression in human endothelial and epithelial cells by up-regulating TLR3 expression. J Immunol. 2005;174:4289–94.PubMedGoogle Scholar
  51. 51.
    •• Okun E, Griffioen KJ, Mattson MP. Toll-like receptor signaling in neural plasticity and disease. Trends Neurosci. 2011;34:269–81. Very comprehensive summary of Toll-like receptor functions.PubMedCrossRefGoogle Scholar
  52. 52.
    Okun E, Griffioen KJ, Lathia JD, Tang SC. Toll-like receptors in neurodegeneration. Brain Res. 2009;59:278–92.CrossRefGoogle Scholar
  53. 53.
    Guo Y, Audry M, Ciancanelli M, Alsina L, Azevedo J, Herman M, et al. Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity. J Exp Med. 2011;208:2083–98.PubMedCrossRefGoogle Scholar
  54. 54.
    Sancho-Shimizu V, deDiego RP, Lorenzo L, Halwani R, et al. Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency. J Clin Invest. 2011;121:4889.PubMedCrossRefGoogle Scholar
  55. 55.
    Herman M, Ciancanelli M, Ou YH, Lorenzo L, Klaudel-Dreszler M, Pauwels E, et al. Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood. J Exp Med. 2012;209:1567–82.PubMedCrossRefGoogle Scholar
  56. 56.
    Zhang S-Y, Jouanguy E, Ugolini S, Smahi A, Elain G, Romero P, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007;317:1522–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Leib DA. Herpes simplex virus encephalitis: Toll-free access to the brain. Cell Host Microbe. 2012;12:731–2.PubMedCrossRefGoogle Scholar
  58. 58.
    Lafaille FG, Pessach IM, Zhang S-Y, Ciancanelli MJ, Herman M, Abhyankar A, et al. Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells. Nature. 2012;491:769–73.PubMedGoogle Scholar
  59. 59.
    Zhang S-Y, Herman M, Ciancanelli MJ, de Diego RP, Sancho-Shimizu V, Abel L, et al. TLR3 immunity to infection in mice and humans. Curr Opin Immunol. 2013;25:19–33.PubMedCrossRefGoogle Scholar
  60. 60.
    Perales-Linares R, Navas-Martin S. Toll-like receptor 3 in viral pathogenesis: friend or foe? Immunology. 2013;140:153–67.PubMedCrossRefGoogle Scholar
  61. 61.
    Voskoboinik I, Smyth MJ, Trapani JA. Perforin-mediated target-cell death and immune homeostasis. Nat Rev Immunol. 2006;6:940–52.PubMedCrossRefGoogle Scholar
  62. 62.
    Smyth MJ, Trapani JA. Granzymes: exogenous porteinases that induce target cell apoptosis. Immunol Today. 1995;16:202–6.PubMedCrossRefGoogle Scholar
  63. 63.
    Barber GN. Host defense, viruses and apoptosis. Cell Death Differ. 2001;8:113–26.PubMedCrossRefGoogle Scholar
  64. 64.
    Joly E, Mucke L, Oldstone M. Viral persistence in neurons explained by lack of major histocompatibility class I expression. Science. 1991;253:1283–5.PubMedCrossRefGoogle Scholar
  65. 65.
    Oldstone MB. Molecular anatomy of viral persistence. J Virol. 1991;65:6381.PubMedGoogle Scholar
  66. 66.
    Knickelbein JE, Hendricks RL, Charukamnoetkanok P. Management of herpes simplex virus stromal keratitis: an evidence-based review. Survey Ophthalmol. 2009;54:226–34.CrossRefGoogle Scholar
  67. 67.
    Maini MK, Boni C, Lee CK, Larrubia JR, Reignat S, Ogg GS, et al. The role of virus-specific Cd8+ cells in liver damage and viral control during persistent hepatitis b virus infection. J Exp Med. 2000;191:1269–80.PubMedCrossRefGoogle Scholar
  68. 68.
    Cerny A, Chisari FV. Pathogenesis of chronic hepatitis C: Immunological features of hepatic injury and viral persistence. Hepatology. 1999;30:595–601.PubMedCrossRefGoogle Scholar
  69. 69.
    Steiner I, Budka H, Chaudhuri A, Koskiniemi M, Sainio K, Salonen O, et al. Viral meningoencephalitis: a review of diagnostic methods and guidelines for management. Eur J Neurol. 2010;17:999–e57.PubMedCrossRefGoogle Scholar
  70. 70.
    Cinque P, Cleator GM, Weber T, Monteyne P, Sindic CJ, van Loon AM. The role of laboratory investigation in the diagnosis and management of patients with suspected herpes simplex encephalitis: a consensus report. The EU Concerted Action on Virus Meningitis and Encephalitis. J Neurol Neurosurg Psychiatry. 1996;61:339–45.PubMedCrossRefGoogle Scholar
  71. 71.
    Benninger F, Steiner I. Steroids in bacterial meningitis: yes. J Neural Transm. 2013;120:339–42.PubMedCrossRefGoogle Scholar
  72. 72.
    Quagliarello V, Scheld WM. Infectious disease: do steroids benefit patients with bacterial meningitis? Nat Rev Neurol. 2010;:529–30.Google Scholar
  73. 73.
    Jacobs DH. Herpes simplex virus encephalitis following corticosteroids and cranial irradiation. Neurology. 1999;52:1106.CrossRefGoogle Scholar
  74. 74.
    Thompson KA, Blessing WW, Wesselingh SL. Herpes simplex replication and dissemination is not increased by corticosteroid treatment in a rat model of focal Herpes encephalitis. J Neurovirol. 2000;6:25–32.PubMedCrossRefGoogle Scholar
  75. 75.
    Meyding-Lamadé UK, Oberlinner C, Rau PR. Experimental herpes simplex virus encephalitis: a combination therapy of acyclovir and glucocorticoids reduces long-term magnetic resonance imaging abnormalities. J Neurovirol. 2003;9:118–25.PubMedGoogle Scholar
  76. 76.
    Almalki DM, Al-Suwaidan FB. Steroid pulse therapy in herpes simplex encephalitis. Neurosciences (Riyadh). 2013;18:276–7.PubMedGoogle Scholar
  77. 77.
    Kamei S. Evaluation of combination therapy using aciclovir and corticosteroid in adult patients with herpes simplex virus encephalitis. J Neurol Neurosurg Psychiatry. 2005;76:1544–9.PubMedCrossRefGoogle Scholar
  78. 78.
    Lizarraga KJ, Alexandre LC, Ramos-Estebanez C, Merenda A. Are steroids a beneficial adjunctive therapy in the immunosuppressed patient with herpes simplex virus encephalitis? Case Rep Neurol. 2013;5:52–5.PubMedCrossRefGoogle Scholar
  79. 79.
    • Martinez-Torres F, Menon S, Pritsch M, Victor N, Jenetzky E, Jensen K, et al. German trial of Acyclovir and corticosteroids in Herpes-simplex-virus-encephalitis (GACHE): a multicenter, multinational, randomized, double-blind, placebo-controlled German, Austrian and Dutch trial. BMC Neurol. 2008;8:40. Initial description of the GACHE trial; still awaiting results.PubMedCrossRefGoogle Scholar
  80. 80.
    VanLandingham KE, Marsteller HB. Relapse of herpes simplex encephalitis after conventional acyclovir therapy. JAMA. 1988;259:1051–3.PubMedCrossRefGoogle Scholar
  81. 81.
    Ito Y, Kimura H, Yabuta Y, Ando Y. Exacerbation of herpes simplex encephalitis after successful treatment with acyclovir. Clin Infect Dis. 2000;30:185–7.PubMedCrossRefGoogle Scholar
  82. 82.
    Kimura H, Aso K, Kuzushima K, Hanada N. Relapse of herpes simplex encephalitis in children. Pediatrics. 1992;89:891–4.PubMedGoogle Scholar
  83. 83.
    Sköldenberg B, Aurelius E, Hjalmarsson A, Sabri F. Incidence and pathogenesis of clinical relapse after herpes simplex encephalitis in adults. J Neurol. 2006;253:163–70.PubMedCrossRefGoogle Scholar
  84. 84.
    Barthez-Carpentier MA, Rozenberg F. Relapse of herpes simplex encephalitis. J Child Neurol. 1995;10:363–8.PubMedCrossRefGoogle Scholar
  85. 85.
    Gable MS, Sheriff H, Dalmau J. The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California. Clin Infect Dis. 2012;54:899–904.PubMedCrossRefGoogle Scholar
  86. 86.
    Armangue T, Titulaer MJ, Málaga I, Bataller L. Pediatric anti-N-methyl-D-aspartate receptor encephalitis—clinical analysis and novel findings in a series of 20 patients. J Pediatr. 2013;162:850–6.PubMedCrossRefGoogle Scholar
  87. 87.
    Berger JR, Houff S. Neurological complications of herpes simplex virus type 2 infection. Arch Neurol. 2008;65:596–600.PubMedCrossRefGoogle Scholar
  88. 88.
    Logan SAE, MacMahon E. Viral meningitis. BMJ. 2008;336:36–40.PubMedCrossRefGoogle Scholar
  89. 89.
    Thompson C, Whitley R. Neonatal herpes simplex virus infections: where are we now? Adv Exp Med Biol. 2011;697:221–30.PubMedCrossRefGoogle Scholar
  90. 90.
    James SH, Kimberlin DW, Whitley RJ. Antiviral therapy for herpesvirus central nervous system infections: Neonatal herpes simplex virus infection, herpes simplex encephalitis, and congenital cytomegalovirus infection. Antiviral Res. 2009;83:207–13.PubMedCrossRefGoogle Scholar
  91. 91.
    Whitley R. Neonatal herpes simplex virus infection. Curr Opin Infect Dis. 2004;17:243–6.PubMedCrossRefGoogle Scholar
  92. 92.
    Stanberry LR, Spruance SL, Cunningham AL, Bernstein DI, Mindel A, Sacks S, et al. Glycoprotein-D-adjuvant vaccine to prevent genital herpes. N Engl J Med. 2002;347:1652–61.PubMedCrossRefGoogle Scholar
  93. 93.
    Belshe RB, Leone PA, Bernstein DI. Efficacy results of a trial of a herpes simplex vaccine. N Engl J Med. 2012;366:34–43.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of NeurologyRabin Medical CenterPetach TikvaIsrael

Personalised recommendations