Journal of NeuroVirology

, Volume 17, Issue 6, pp 570–577 | Cite as

Investigation of varicella-zoster virus neurotropism and neurovirulence using SCID mouse–human DRG xenografts



Varicella-zoster virus (VZV) is a medically important human alphaherpesvirus. Investigating pathogenic mechanisms that contribute to VZV neurovirulence are made difficult by a marked host restriction. Our approach to investigating VZV neurotropism and neurovirulence has been to develop a mouse–human xenograft model in which human dorsal root ganglia (DRG) are maintained in severe compromised immunodeficient (SCID) mice. In this review, we will describe our key findings using this model in which we have demonstrated that VZV infection of SCID DRG xenograft results in rapid and efficient spread, enabled by satellite cell infection and polykaryon formation, which facilitates robust viral replication and release of infectious virus. In neurons that persist following this acute replicative phase, VZV genomes are present at low frequency with limited gene transcription and no protein synthesis, a state that resembles VZV latency in the natural human host. VZV glycoprotein I and interaction between glycoprotein I and glycoprotein E are critical for neurovirulence. Our work demonstrates that the DRG model can reveal characteristics about VZV replication and long-term persistence of latent VZV genomes in human neuronal tissues, in vivo, in an experimental system that may contribute to our knowledge of VZV neuropathogenesis.


Varicella-zoster virus Neuropathogenesis Neurotropism Glycoprotein E Glycoprotein I SCID 



We thank past and present members of the Arvin lab, many of whom contributed to these experiments, especially Mike Reichelt, Stefan Oliver, Xibing Che, Jaya Rajamani, Preeti Sikka, and Michelle Lai. We also thank Dr. Raymond A. Sobel, Professor of Pathology, Stanford University School of Medicine, for helpful discussions and collaborations. This work was supported by grants AI20459 and AI053846 from the National Institute of Allergy and Infectious Diseases and grant CA049605 from the National Cancer Institute.


  1. Arvin AM, Moffat JF, Sommer M, Oliver S, Che X, Vleck S, Zerboni L, Ku CC (2010) Varicella-zoster virus T cell tropism and the pathogenesis of skin infection. Curr Top Microbiol Immunol 342:189–209PubMedCrossRefGoogle Scholar
  2. Berarducci B, Ikoma M, Stamatis S, Sommer M, Grose C, Arvin AM (2006) Essential functions of the unique N-terminal region of the varicella-zoster virus glycoprotein E ectodomain in viral replication and in the pathogenesis of skin infection. J Virol 80:9481–9496PubMedCrossRefGoogle Scholar
  3. Berarducci B, Rajamani J, Zerboni L, Che X, Sommer M, Arvin AM (2010) Functions of the unique N-terminal region of glycoprotein E in the pathogenesis of varicella-zoster virus infection. Proc Natl Acad Sci USA 107:282–287PubMedCrossRefGoogle Scholar
  4. Card JP, Whealy ME, Robbins AK, Enquist LW (1992) Pseudorabies virus envelope glycoprotein gI influences both neurotropism and virulence during infection of the rat visual system. J Virol 66:3032–3041PubMedGoogle Scholar
  5. Ch’ng TH, Enquist LW (2005) Efficient axonal localization of alphaherpesvirus structural proteins in cultured sympathetic neurons requires viral glycoprotein E. J Virol 79:8835–8846PubMedCrossRefGoogle Scholar
  6. Cohen J, Straus S, Arvin A (2007) Varicella-zoster virus replication, pathogenesis, and management. In: Knipe D, Howley P (eds) Fields virology. Lippincott-Williams & Wilkins, Philadelphia, pp 2774–2818Google Scholar
  7. Cohrs RJ, Barbour M, Gilden DH (1996) Varicella-zoster virus (VZV) transcription during latency in human ganglia: detection of transcripts mapping to genes 21, 29, 62, and 63 in a cDNA library enriched for VZV RNA. J Virol 70:2789–2796PubMedGoogle Scholar
  8. Cohrs RJ, Randall J, Smith J, Gilden DH, Dabrowski C, van Der Keyl H, Tal-Singer R (2000) Analysis of individual human trigeminal ganglia for latent herpes simplex virus type 1 and varicella-zoster virus nucleic acids using real-time PCR. J Virol 74:11464–11471PubMedCrossRefGoogle Scholar
  9. Dingwell KS, Brunetti CR, Hendricks RL, Tang Q, Tang M, Rainbow AJ, Johnson DC (1994) Herpes simplex virus glycoproteins E and I facilitate cell-to-cell spread in vivo and across junctions of cultured cells. J Virol 68:834–845PubMedGoogle Scholar
  10. Dingwell KS, Doering LC, Johnson DC (1995) Glycoproteins E and I facilitate neuron-to-neuron spread of herpes simplex virus. J Virol 69:7087–7098PubMedGoogle Scholar
  11. Grinfeld E, Kennedy PG (2004) Translation of varicella-zoster virus genes during human ganglionic latency. Virus Genes 29:317–319PubMedCrossRefGoogle Scholar
  12. Hufner K, Derfuss T, Herberger S, Sunami K, Russell S, Sinicina I, Arbusow V, Strupp M, Brandt T, Theil D (2006) Latency of alpha-herpes viruses is accompanied by a chronic inflammation in human trigeminal ganglia but not in dorsal root ganglia. J Neuropathol Exp Neurol 65:1022–1030PubMedCrossRefGoogle Scholar
  13. Ito H, Sommer MH, Zerboni L, He H, Boucaud D, Hay J, Ruyechan W, Arvin AM (2003) Promoter sequences of varicella-zoster virus glycoprotein I targeted by cellular transactivating factors Sp1 and USF determine virulence in skin and T cells in SCIDhu mice in vivo. J Virol 77:489–498PubMedCrossRefGoogle Scholar
  14. Jones JO, Sommer M, Stamatis S, Arvin AM (2006) Mutational analysis of the varicella-zoster virus ORF62/63 intergenic region. J Virol 80:3116–3121PubMedCrossRefGoogle Scholar
  15. Kennedy PG, Grinfeld E, Gow JW (1998) Latent varicella-zoster virus is located predominantly in neurons in human trigeminal ganglia. Proc Natl Acad Sci USA 95:4658–4662Google Scholar
  16. Kennedy PG, Grinfeld E, Gow JW (1999) Latent varicella-zoster virus in human dorsal root ganglia. Virology 258:451–454Google Scholar
  17. Ku CC, Padilla JA, Grose C, Butcher EC, Arvin AM (2002) Tropism of varicella-zoster virus for human tonsillar CD4(+) T lymphocytes that express activation, memory, and skin homing markers. J Virol 76:11425–11433PubMedCrossRefGoogle Scholar
  18. Ku CC, Zerboni L, Ito H, Graham BS, Wallace M, Arvin AM (2004) Varicella-zoster virus transfer to skin by T Cells and modulation of viral replication by epidermal cell interferon-alpha. J Exp Med 200:917–925PubMedCrossRefGoogle Scholar
  19. Li Q, Ali MA, Cohen JI (2006) Insulin degrading enzyme is a cellular receptor mediating varicella-zoster virus infection and cell-to-cell spread. Cell 127:305–316PubMedCrossRefGoogle Scholar
  20. Li Q, Krogmann T, Ali MA, Tang WJ, Cohen JI (2007) The amino terminus of varicella-zoster virus (VZV) glycoprotein E is required for binding to insulin-degrading enzyme, a VZV receptor. J Virol 81:8525–8532PubMedCrossRefGoogle Scholar
  21. Lungu O, Panagiotidis CA, Annunziato PW, Gershon AA, Silverstein SJ (1998) Aberrant intracellular localization of Varicella-Zoster virus regulatory proteins during latency. Proc Natl Acad Sci USA 95:7080–7085PubMedCrossRefGoogle Scholar
  22. Mahalingam R, Wellish M, Cohrs R, Debrus S, Piette J, Rentier B, Gilden DH (1996) Expression of protein encoded by varicella-zoster virus open reading frame 63 in latently infected human ganglionic neurons. Proc Natl Acad Sci USA 93:2122–2124Google Scholar
  23. Marmigere F, Ernfors P (2007) Specification and connectivity of neuronal subtypes in the sensory lineage. Nat Rev Neurosci 8:114–127PubMedCrossRefGoogle Scholar
  24. Moffat J, Mo C, Cheng JJ, Sommer M, Zerboni L, Stamatis S, Arvin AM (2004) Functions of the C-terminal domain of varicella-zoster virus glycoprotein E in viral replication in vitro and skin and T-cell tropism in vivo. J Virol 78:12406–12415PubMedCrossRefGoogle Scholar
  25. Montelius A, Marmigere F, Baudet C, Aquino JB, Enerback S, Ernfors P (2007) Emergence of the sensory nervous system as defined by Foxs1 expression. Differentiation 75:404–417PubMedCrossRefGoogle Scholar
  26. Nagel MA, Choe A, Traktinskiy I, Cordery-Cotter R, Gilden D, Cohrs RJ (2011) Varicella-zoster virus transcriptome in latently infected human ganglia. J Virol 85:2276–2287PubMedCrossRefGoogle Scholar
  27. Oliver SL, Zerboni L, Sommer M, Rajamani J, Arvin AM (2008) Development of recombinant varicella-zoster viruses expressing luciferase fusion proteins for live in vivo imaging in human skin and dorsal root ganglia xenografts. J Virol Methods 154:182–193PubMedCrossRefGoogle Scholar
  28. Pevenstein SR, Williams RK, McChesney D, Mont EK, Smialek JE, Straus SE (1999) Quantitation of latent varicella-zoster virus and herpes simplex virus genomes in human trigeminal ganglia. J Virol 73:10514–10518PubMedGoogle Scholar
  29. Polcicova K, Goldsmith K, Rainish BL, Wisner TW, Johnson DC (2005) The extracellular domain of herpes simplex virus gE is indispensable for efficient cell-to-cell spread: evidence for gE/gI receptors. J Virol 79:11990–12001PubMedCrossRefGoogle Scholar
  30. Reichelt M, Zerboni L, Arvin AM (2008) Mechanisms of varicella-zoster virus neuropathogenesis in human dorsal root ganglia. J Virol 82:3971–3983PubMedCrossRefGoogle Scholar
  31. Saldanha CE, Lubinski J, Martin C, Nagashunmugam T, Wang L, van Der Keyl H, Tal-Singer R, Friedman HM (2000) Herpes simplex virus type 1 glycoprotein E domains involved in virus spread and disease. J Virol 74:6712–6719PubMedCrossRefGoogle Scholar
  32. Theil D, Derfuss T, Paripovic I, Herberger S, Meinl E, Schueler O, Strupp M, Arbusow V, Brandt T (2003) Latent herpesvirus infection in human trigeminal ganglia causes chronic immune response. Am J Pathol 163:2179–2184PubMedCrossRefGoogle Scholar
  33. Tirabassi RS, Enquist LW (2000) Role of the pseudorabies virus gI cytoplasmic domain in neuroinvasion, virulence, and posttranslational N-linked glycosylation. J Virol 74:3505–3516PubMedCrossRefGoogle Scholar
  34. Wang K, Lau TY, Morales M, Mont EK, Straus SE (2005) Laser-capture microdissection: refining estimates of the quantity and distribution of latent herpes simplex virus 1 and varicella-zoster virus DNA in human trigeminal ganglia at the single-cell level. J Virol 79:14079–14087PubMedCrossRefGoogle Scholar
  35. Zerboni L, Ku CC, Jones CD, Zehnder JL, Arvin AM (2005) Varicella-zoster virus infection of human dorsal root ganglia in vivo. Proc Natl Acad Sci USA 102:6490–6495PubMedCrossRefGoogle Scholar
  36. Zerboni L, Reichelt M, Jones CD, Zehnder JL, Ito H, Arvin AM (2007) From the cover: aberrant infection and persistence of varicella-zoster virus in human dorsal root ganglia in vivo in the absence of glycoprotein I. Proc Natl Acad Sci USA 104:14086–14091PubMedCrossRefGoogle Scholar
  37. Zerboni L, Reichelt M, Arvin A (2010) Varicella-zoster virus neurotropism in SCID mouse-human dorsal root ganglia xenografts. Curr Top Microbiol Immunol 342:255–276PubMedCrossRefGoogle Scholar
  38. Zerboni L, Berarducci B, Rajamani J, Jones CD, Zehnder JL, Arvin A (2011a) Varicella-zoster virus glycoprotein E is a critical determinant of virulence in the SCID mouse-human model of neuropathogenesis. J Virol 85:98–111PubMedCrossRefGoogle Scholar
  39. Zerboni L, Sobel RA, Lai M, Triglia R, Steain M, Abendroth A, Arvin A (2011b) Apparent expression of varicella-zoster virus protein in latency resulting from reactivity of murine and rabbit antibodies with human blood group A determinants in sensory neurons. J Virology (in press)Google Scholar
  40. Zhu Z, Hao Y, Gershon MD, Ambron RT, Gershon AA (1996) Targeting of glycoprotein I (gE) of varicella-zoster virus to the trans-Golgi network by an AYRV sequence and an acidic amino acid-rich patch in the cytosolic domain of the molecule. J Virol 70:6563–6575PubMedGoogle Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2011

Authors and Affiliations

  1. 1.Department of PediatricsStanford University School of MedicineStanfordUSA
  2. 2.Department of Microbiology and ImmunologyStanford University School of MedicineStanfordUSA

Personalised recommendations