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38 - VZV: molecular basis of persistence (latency and reactivation)

from Part III - Pathogenesis, clinical disease, host response, and epidemiology: VZU

Published online by Cambridge University Press:  24 December 2009

By
Jeffrey I. Cohen
Edited by
Ann Arvin ,
Gabriella Campadelli-Fiume ,
Edward Mocarski ,
Patrick S. Moore ,
Bernard Roizman ,
Richard Whitley  and
Koichi Yamanishi
Jeffrey I. Cohen
Affiliation:
Laboratory of Clinical Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
Ann Arvin
Affiliation:
Stanford University, California
Gabriella Campadelli-Fiume
Affiliation:
Università degli Studi, Bologna, Italy
Edward Mocarski
Affiliation:
Emory University, Atlanta
Patrick S. Moore
Affiliation:
University of Pittsburgh
Bernard Roizman
Affiliation:
University of Chicago
Richard Whitley
Affiliation:
University of Alabama, Birmingham
Koichi Yamanishi
Affiliation:
University of Osaka, Japan
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Summary

Primary infection with varicella-zoster virus (VZV) causes varicella manifested by fever and a vesicular rash. During primary infection the virus disseminates in lymphocytes to the skin and other organs, and replicates in and establishes a latent infection in the nervous system (Croen et al., 1988). Early studies demonstrated viral DNA in human trigeminal and dorsal root ganglia by in situ hybridization and Southern blotting (Gilden et al., 1983, 1987; Hyman et al., 1983). More recent studies, using PCR, have demonstrated latent VZV in multiple cranial nerve, dorsal root, and autonomic ganglia (Furuta et al., 1992, 1997; Gilden et al., 2001; Mahalingham et al., 1990). The virus can reactivate from these sites to cause herpes zoster.

The structure of the VZV genome during latency is not certain. Clarke et al. (1995) performed PCR on human ganglia DNA using pairs of primers specific for the unique long internal and terminal regions of the genome. Analysis of the ratio of the signals of the PCR products indicated that the termini of the genome are adjacent during latency, suggesting that the VZV genome is probably episomal.

Site of VZV latency

A number of studies have attempted to identify the cell type in which VZV is latent in human ganglia (Table 38.1). While early studies using in situ hybridization suggested that the virus was present in neurons (Hyman et al., 1983; Gilden et al., 1987), other studies suggested that viral RNA was latent exclusively in satellite cells that surround the neurons (Croen et al., 1988).

Type
Chapter
Information
Human Herpesviruses
Biology, Therapy, and Immunoprophylaxis
 , pp. 689 - 699
Publisher: Cambridge University Press
Print publication year: 2007

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References

Annunziato, P., LaRussa, P., Lee, P.et al. (1998). Evidence of latent varicella-zoster virus in rat dorsal root gangliaJ. Infect. Dis., 178 (Suppl 1), S48–S51.CrossRefGoogle ScholarPubMed
Arvin, A. M., Sharp, M., Moir, M.et al. (2002). Memory cytotoxic T cell responses to viral tegument and regulatory proteins encoded by open reading frames 4, 10, 29, and 62 of varicella-zoster virus. Viral Immunol., 15, 507–516.CrossRefGoogle ScholarPubMed
, Assouline J. G., Levin, M. J., Major, E. O., Forghani, B., Straus, S. E., and Ostrove, J. M. (1990). Varicella-zoster virus infection of human astrocytes, Schwann cells, and neurons. Virology, 179, 834–844.Google Scholar
Baiker, A., Fabel, K., Cozzio, A.et al. (2004). Varicella-zoster virus infection of human neural cells in vivo. Proc. Natl Acad. Sci. USA, 101, 10792–10797.CrossRefGoogle ScholarPubMed
Bontems, S., Valentin, E., Baudoux, L., Rentier, B., Sadzot-Delvaux, C., and Piette, J. (2002). Phosphorylation of varicella-zoster virus IE63 protein by casein kinases influences its cellular localization and gene regulation activity. J. Biol. Chem., 277, 21050–21060.CrossRefGoogle ScholarPubMed
Boucaud, D., Yoshitake, H., Hay, J., and Ruyechan, W. (1998). The varicella-zoster virus (VZV) open-reading frame 29 protein acts as a modulator of a late VZV gene promoter. J. Infect. Dis., 178 (Suppl. 1), S34–S38.CrossRefGoogle ScholarPubMed
Brunell, P. A., Ren, L. C., Cohen, J. I., and Straus, S. E. (1999). Viral gene expression in rat trigeminal ganglia following neonatal infection with varicella-zoster virus. J. Med. Virol., 58, 286–290.3.0.CO;2-E>CrossRefGoogle ScholarPubMed
, Chen J. J., Gershon, A. A., Li, Z. S., Lungu, O., and Gershon, M. D. (2003). Latent and lytic infection of isolated guinea pig enteric ganglia by varicella zoster virus. J. Med. Virol., 70 (Suppl. 1), S71–S78.Google Scholar
Clarke, P., Beer, T., Cohrs, R., and Gilden, D. H. (1995). Configuration of latent varicella-zoster virus DNA. J. Virol., 69, 8151–8154.Google ScholarPubMed
Clarke, P., Matlock, W. L., Beer, T. and Gilden, D. H. (1996). A simian varicella virus (SVV) homolog to varicella-zoster virus gene 21 is expressed in monkey ganglia latently infected with SVV. J. Virol., 70, 5711–5715.Google ScholarPubMed
Cohen, J. I., Cox, E., Pesnicak, L., Srinivas, S., and Krogmann T. (2004). The varicellazoster virus ORF63 latency-associated protein is critical for establishment of latency. J. Virol., 78, 11833–11840.Google Scholar
Cohen, J. I., Krogmann, T., Bontems, S., Sadzot-Delvaux, C., and Pesnicak, L. (2005a). Regions of the varicella-zoster virus open reading from 63 latency-associated protein important for replication in vitro are also critical for efficient establishment of latency. J. Virol., 79, 5069–5077.Google Scholar
Cohen, J. I. and Straus, S. E. (2001). Varicella-zoster virus and its replication. In Fields Virology, ed. Knipe, D. M., Howley, P. M.et al. pp. 2707–2730. Philadelphia, PA: Lippincott-Williams & Wilkins.Google Scholar
Cohen J. I., Krogmann, T., Ross, J. P.et al. (2005b). Varicella-zoster virus ORF4 latency-associated protein is important for establishment of latency. J. Virol., 79, 6969–6975.Google Scholar
, Cohrs R. J., Barbour, M. B., and Gilden, D. H. (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, 2789–2796.Google Scholar
Cohrs, R. J., Randall, J., Smith, J.et al. (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, 11464–11471.CrossRefGoogle ScholarPubMed
, Cohrs R. J., Gilden, D. H., Kinchington, P. R., Grinfeld, E., and Kennedy, P. G. E. (2003). Varicella-zoster virus gene 66 transcription and translation in latently infected human ganglia. J. Virol., 77, 6660–6665.Google Scholar
Croen, K. D., Ostrove, J. M., Dragovic, L. J., and Straus, S. E. (1988). Patterns of gene expression and sites of latency in human nerve ganglia are different for varicella-zoster and herpes simplex viruses. Proc. Natl Acad. Sci. USA, 85, 9773–9777.CrossRefGoogle ScholarPubMed
Debrus, S., Sadzot-Delvaux, C., Nikkels, A. F., Piette, J., and Rentier, B. (1995). Varicella-zoster virus gene 63 encodes an immediate-early protein that is abundantly expressed during latency. J. Virol., 69, 3240–3245.Google ScholarPubMed
Dueland, A. N., Rannenbery-Nilsen, T., and Degre, M. (1995). Detection of latent varicella-zoster virus DNA and human gene sequences in human trigeminal ganglia by in situ amplification combined with in situ hybridization. Arch. Virol., 140, 2055–2066.CrossRefGoogle ScholarPubMed
Efstathiou, S. E., Minson, A. C., Field, H. J., Anderson, J. R., and Wildy, P. (1986). Detection of herpes simplex virus-specific DNA sequences in latently infected mice and humans. J. Virol., 57, 446–455.Google ScholarPubMed
Furuta, Y., Takasu, T., Fukuda, S.et al. (1992). Detection of varicella-zoster virus DNA in human geniculate ganglia by polymerase chain reaction. J. Infect. Dis., 166, 1157–1159.CrossRefGoogle ScholarPubMed
Furuta, Y., Takasu, T., Suzuki, S., Fukuda, S., Inuyama, Y., and Nagashima, K. (1997). Detection of latent varicella-zoster virus infection in human vestibular and spiral ganglia. J. Med. Virol., 51, 214–216.3.0.CO;2-K>CrossRefGoogle ScholarPubMed
Gary, L., Gilden, D. H., and Cohrs, R. J. (2006). Epigenetic regulation of varicella-zoster virus open reading frame 62 and 63 in latently infected human trigeminal ganglia. J. Virol., 80, 4921–4926.CrossRefGoogle ScholarPubMed
Gilden, D. H., Vafai, A., Shtram, Y., Becker, Y., Devlin, M., and Wellish, M. (1983). Varicella-zoster virus DNA in human sensory ganglia. Nature, 306, 478–480.CrossRefGoogle ScholarPubMed
Gilden, D. H., Rosenman, Y., Murray, R., Devlin, A., and Vafai, A. (1987). Detection of varicella-zoster virus nucleic acid in neurons of normal human thoracic ganglia. Ann. Neural., 22, 377–380.CrossRefGoogle ScholarPubMed
Gilden, D. H., Gesser, R., Smith, J.et al. (2001). Presence of VZV and HSV-1 DNA in human nodose and celiac ganglia. Virus Genes, 23, 145–147.CrossRefGoogle ScholarPubMed
Gray, W. L. (2004). Simian varicella: a model for human varicella-zoster virus infection. Rev. Med. Virol., 14, 363–381.CrossRefGoogle Scholar
Gray, W. L., Starnes, B., White, M. W., and Mahalingam, R. (2001). The DNA sequence of the simian varicella virus genome. Virology, 284, 123–130.CrossRefGoogle ScholarPubMed
Grinfeld, E. and Kennedy, P. G. E. (2004). Translation of varicella-zoster virus genes during human ganglionic latency. Virus Genes, 29, 317–319.CrossRefGoogle ScholarPubMed
Grinfeld, E., Sadzot-Delvaux, C., and Kennedy, P. G. E. (2004). Varicella-zoster virus proteins encoded by open reading frames 14 and 67 are both dispensable for the establishment of latency in a rat model. Virology, 323, 85–90.CrossRefGoogle Scholar
Hood, C. Cunningham, A. L., Slobedman, B., Boadle, R. A., and Abendroth, A. (2003). Varicella-zoster virus-infected human sensory neurons are resistant to apoptosis, yet human foreskin fibroblasts are susceptible: evidence for a cell-type-specific apoptotic response. J. Virol., 77, 12852–12864.Google Scholar
Hood, C., Cunningham, A. L., Slobedman, B., et al. (2006). Varicella-zoster virus ORF63 inhibits apoptosis of primary human neurons. J. Virol., 80, 1025–1031.CrossRefGoogle ScholarPubMed
Hoover, S. E., Cohrs, R. J., Rangel, Z. G., Gilden, D. H., Munson, P., and Cohen, J. I. (2006). Downregulation of varicella-zoster virus (VZV) immediate-early ORF62 transcription by VZV ORF63 correlates with virus replication in vitro and with latency. J. Virol., 80, 3459–3468.CrossRefGoogle ScholarPubMed
Hyman, R. W., Ecker, J. R., and Tenser, R. B. (1983). Varicella-zoster virus RNA in human trigeminal ganglia. Lancet, ii, 814–816.CrossRefGoogle Scholar
Kennedy, P. G., Grinfeld, E., Bontems, S., and Sadzot-Delvaux, C. (2001). Varicella-zoster virus gene expression in latently infected rat dorsal root ganglia. Virology, 289, 218–223.CrossRefGoogle ScholarPubMed
Kennedy, P. G., Grinfeld, E., Traina-Dorge, V., Gilden, D. H., and Mahalingam, R. (2004). Neuronal localization of simian varicella virus DNA in ganglia of naturally infected African green monkeys. Virus Genes, 28, 273–276.CrossRefGoogle ScholarPubMed
Kennedy, P. G. E., Grinfield, E., and Gow, J. W. (1998). Latent varicella-zoster virus is located predominantly in neurons in human trigeminal ganglia. Proc. Natl Acad. Sci. USA, 95, 4658–4662.CrossRefGoogle ScholarPubMed
Kennedy., P. G. E., Grinfeld, E., and Gow, J. W. (1999). Latent varicella-zoster virus in human dorsal root ganglia. Virology, 258, 451–454.CrossRefGoogle ScholarPubMed
Kennedy, P. G. E., Grinfeld, E., and Bell, J. E. (2000). Varicella-zoster virus gene expression in latently infected and explanted human ganglia. J. Virol., 74, 11893–11898.CrossRefGoogle ScholarPubMed
Kinchington, P. R., Fite, K, and Turse, S. E. (2000). Nuclear accumulation of IE62, the varicella-zoster virus (VZV) major transcriptional regulatory protein, is inhibited by phosphorylation mediated by the VZV open reading frame 66 protein kinase. J. Virol., 74, 2265–2277.CrossRefGoogle ScholarPubMed
Kress, M. and Fickenscher, H. (2001). Infection by human varicella-zoster virus confers norepinephrine sensitivity to sensory neurons from rat dorsal root ganglia. FASEB J., 15, 1037–1043.CrossRefGoogle ScholarPubMed
Kristie, T. M., Vogel, J. L., and Sears, A. E. (1999). Nuclear localization of the C1 factor (host cell factor) in sensory neurons correlates with reactivation of herpes simplex from latency. Proc. Natl Acad. Sci., 96, 1229–1233.CrossRefGoogle ScholarPubMed
LaGuardia, J. J., Cohrs, R. J., and Gilden, D. H. (1999). Prevalence of varicella-zoster virus DNA in dissociated human trigeminal ganglion neurons and nonneuronal cells. J. Virol., 73, 8571–8577.Google ScholarPubMed
Levin, M. J., Cai, G. Y., Manchak, M. D., and Pizer, L. I. (2003). Varicella-zoster virus DNA in cells isolated from human trigeminal ganglia. J. Virol., 77, 6979–6987.CrossRefGoogle ScholarPubMed
Lowry, P. W., Sabella, C., Koropchak, C. M.et al. (1993). Investigation of the pathogenesis of varicella-zoster virus infection in guinea pigs by using polymerase chain reactionJ. Infect. Dis., 167, 78–83.CrossRefGoogle ScholarPubMed
Lungu, O., Annunziato, P. W., Gershon, A.et al. (1995). Reactivated and latent varicella-zoster virus in human dorsal root ganglia. Proc. Natl Acad. Sci. USA, 92, 10980–10984.CrossRefGoogle ScholarPubMed
Lungu, O., Panagiotidis, C. A., Annunziato, P. W., Gershon, A. A., and Silverstein, S. J. (1998). Aberrant intracellular localization of varicella-zoster virus regulatory proteins during latency. Proc. Natl Acad. Sci. USA, 95, 7080–7085.CrossRefGoogle ScholarPubMed
Mahalingam, R., Wellish, M., Wolf, Q.et al. (1990). Latent varicella-zoster virus DNA in human trigeminal and thoracic ganglia. N. Engl. J. Med., 323, 627–631.CrossRefGoogle ScholarPubMed
Mahalingam, R., Smith, D., Wellish, M.et al. (1991). Simian varicella virus DNA in dorsal root ganglia. Proc. Natl Acad. Sci. USA, 88, 2750–2752.CrossRefGoogle ScholarPubMed
Mahalingam, R., Wellish, M., Lederer, D., Forghani, B., Cohrs, R., and Gilden, D. (1993). Quantitation of latent varicella-zoster virus DNA in human trigeminal ganglia by polymerase chain reaction. J. Virol., 67, 2381–2384.Google ScholarPubMed
Mahalingam, R., Wellish, M., Cohrs, R.et al. (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, 2122–2124.CrossRefGoogle ScholarPubMed
Mahalingam, R., Traina-Dorge, V., Wellish, M., Smith, J., and Gilden, D. (2002). Naturally acquired simian varicella virus infection in African green monkeys. J. Virol., 76, 8548–8550.CrossRefGoogle ScholarPubMed
Meier, J. L., Holman, R. P., Croen, K. D., Smialek, J. E., and Straus, S. E. (1993). Varicella-zoster virus transcription in human trigeminal ganglia. Virology, 193, 193–200.CrossRefGoogle ScholarPubMed
Merville-Louis, M. P., Sadzot-Delvaux, S.Delree, P., Piette, J., Moonen, G., and Rentier, B. (1989). Varicella-zoster virus infection of adult rat sensory neurons in vitro. J. Virol., 63 3155–3160.Google ScholarPubMed
Moriuchi, H., Moriuchi, M., and Cohen, J. I. (1995). Proteins and cis-acting elements associated with transactivation of the varicella-zoster virus (VZV) immediate-early gene 62 promoter by VZV open reading frame 10 protein. J. Virol., 69, 4693–4701.Google ScholarPubMed
Oxman, M. N., Levin, M. J., Johnson, G. R.et al. (2005). A vaccine to prevent herpes zoster and postherpetic neuralgia. N. Eng. J. Med., 352, 2271–2284.CrossRefGoogle ScholarPubMed
Patel, Y., Gough, G., Coffin, R. S., Thomas, S., Cohen, J. I., and Latchman, D. S. (1998). Cell type specific repression of the varicella-zoster virus immediate-early gene 62 promoter by the cellular Oct-2 transcription factor. Biochim. Biophys. Acta, 1397, 268–274.CrossRefGoogle ScholarPubMed
Pevenstein, S. R., Williams, R. K., McChesney, D., Mont, E. K., Smialek, J. E., and Straus, S. E. (1999). Quantitation of latent varicella-zoster virus and herpes simplex virus genomes in human trigeminal ganglia. J. Virol., 73, 10514–10518.Google ScholarPubMed
Sadzot-Delvaux, C., Merville-Louis, S., and Delree, M. P. (1990). An in vivo model of varicella-zoster virus latent infection of dorsal root ganglia. J. Neurosci. Res., 26, 83–89.CrossRefGoogle Scholar
Sadzot-Delvaux, C., Debrus, S., Nikkels, A., Piette, J., and Rentier, B. (1995). Varicella-zoster virus latency in the adult rat is a useful model for human latent infection. Neurology, 45 (Suppl. 8), S18–S20.CrossRefGoogle ScholarPubMed
Sadzot-Delvaux, C., Kinchington, P. R., Debrus, S., Rentier, B., and Arvin, A. M. (1997). Recognition of the latency-associated immediate early protein IE63 of varicella-zoster virus by human memory T lymphocytes. J. Immunol., 159, 2802–2806.Google ScholarPubMed
Sato, H., Callanan, L. D., Pesnicak, L., Krogmann, T., and Cohen, J. I. (2002a). Varicella-zoster virus (VZV) ORF17 protein induces RNA cleavage and is critical for replication of VZV at 37°C, but not 33°C. J. Virol., 76, 11012–11023.CrossRefGoogle Scholar
Sato, H., Pesnicak, L., and Cohen, J. I. (2002b). Varicella-zoster virus open reading frame 2 encodes a membrane phosphoprotein that is dispensable for viral replication and for establishment of latency. J. Virol., 76, 3575–3578.CrossRefGoogle Scholar
Sato, H., Pesnicak, L., and Cohen, J. I. (2003a). Use of a rodent model to show that varicella-zoster virus ORF61 is dispensable for establishment of latency. J. Med. Virol., 70 (Suppl 1), S79–S81.CrossRefGoogle Scholar
Sato, H., Pesnicak, L., and Cohen, J. I. (2003b). Varicella-zoster virus ORF47 protein kinase which is required for replication in human T cells, and ORF66 protein kinase which is expressed during latency, are dispensable for establishment of latency. J. Virol., 77, 11180–11185.CrossRefGoogle Scholar
Somekh, E., Tedder, D. G., Vafai, A.et al. (1992). Latency in vitro of varicella-zoster virus in cells derived from human fetal dorsal root ganglia. Pediatr. Res., 32, 699–703.CrossRefGoogle ScholarPubMed
Stallings, C. L., Duigou, G. J., Gershon, A. A., Gershon, M. D., and Silverstein, S. J. (2006). The cellular localization pattern of varicella-zoster virus ORF29p is influenced by proteosome-mediated degradation. J. Virol., 80, 1497–1512.CrossRefGoogle Scholar
Theil, D., Paripovic, I., Derfuss, T.et al. (2003). Dually infected (HSV-1/VZV) single neruons in human trigeminal ganglia. Ann. Neurol., 54, 678–681.CrossRefGoogle Scholar
Vafai, A., Murray, R. S., Wellish, M., Devlin, M., and Gilden, D. H. (1988). Expression of varicella-zoster virus and herpes simplex virus in normal human trigeminal ganglia. Proc. Natl Acad. Sci. USA, 85, 2362–2366.CrossRefGoogle ScholarPubMed
Wang, K., Lau, T. Y., Morales, M., Mont, E. K., and Straus, S. E. (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, 14079–14087.CrossRefGoogle ScholarPubMed
White, T. M., Mahalingam, R., Traina-Dorge, V., and Gilden, D. H. (2002). Simian varicella virus DNA is present and transcribed months after experimental infection of adult African green monkeys. J. Neurovirol., 8, 191–205.CrossRefGoogle ScholarPubMed
Wigdahl, B., Rong, B. L., and Kinney-Thomas, E. (1986). Varicella-zoster virus infection of human sensory neurons. Virology, 152, 384–399.CrossRefGoogle ScholarPubMed
Wroblewska, Z., Valyi-Nagy, T., Otte, J.et al. (1993). A mouse model for varicella-zoster virus latency. Microbiol. Pathogen., 15, 141–151.CrossRefGoogle ScholarPubMed
Xia, D. M., Srinivas, S., Sato, H., Pesnicak, L., Straus, S. E., and Cohen, J. I. (2002). Varicella-zoster virus ORF21, which is expressed during latency, is essential for virus replication but dispensable for establishment of latency. J. Virol., 77, 1211–1218.CrossRefGoogle Scholar
Zerboni, L., Ku, C.-C., Jones, C. D., Zehnder, J. L., and Arvin, A. M. (2005). Varicella-zoster virus infection of human dorsal root ganglia in vivo. Proc. Natl Acad. Sci. USA, 102, 6490–6495.CrossRefGoogle ScholarPubMed
Zuranski, T., Nawar, H., Czechowski, D.et al. (2005). Cell-type-dependent activation of the cellular EF-1α promoter by the varicella-zoster virus IE63 protein. Virology, 338, 35–42.CrossRefGoogle ScholarPubMed

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