Skip to main content

Advertisement

Log in

Simian varicella virus gene expression during acute and latent infection of rhesus macaques

  • Published:
Journal of NeuroVirology Aims and scope Submit manuscript

Abstract

Varicella zoster virus (VZV) is a neurotropic α-herpesvirus that causes chickenpox during primary infection and establishes latency in sensory ganglia. Reactivation of VZV results in herpes zoster and other neurological complications. Our understanding of the VZV transcriptome during acute and latent infection in immune competent individuals remains incomplete. Infection of rhesus macaques with the homologous simian varicella virus (SVV) recapitulates the hallmarks of VZV infection. We therefore characterized the SVV transcriptome by quantitative real-time reverse transcriptase PCR during acute infection in bronchial alveolar lavage (BAL) cells and peripheral blood mononuclear cells, and during latency in sensory ganglia obtained from the same rhesus macaques. During acute infection, all known SVV open reading frames (ORFs) were detected, and the most abundantly expressed ORFs are involved in virus replication and assembly such as the transcriptional activator ORF 63 and the structural proteins ORF 41 and ORF 49. In contrast, latent SVV gene expression is highly restricted. ORF 61, a viral transactivator and latency-associated transcript, is the most prevalent transcript detected in sensory ganglia. We also detected ORFs A, B, 4, 10, 63, 64, 65, 66, and 68 though significantly less frequently than ORF 61. This comprehensive analysis has revealed genes that potentially play a role in the establishment and/or maintenance of SVV latency.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Abendroth A, Lin I, Slobedman B, Ploegh H, Arvin AM (2001) Varicella-zoster virus retains major histocompatibility complex class I proteins in the Golgi compartment of infected cells. J Virol 75:4878–4888

    Article  PubMed  CAS  Google Scholar 

  • Ali MA, Li Q, Fischer ER, Cohen JI (2009) The insulin degrading enzyme binding domain of varicella-zoster virus (VZV) glycoprotein E is important for cell-to-cell spread and VZV infectivity, while a glycoprotein I binding domain is essential for infection. Virology 386:270–279

    Article  PubMed  CAS  Google Scholar 

  • Ambagala AP, Cohen JI (2007) Varicella-zoster virus IE63, a major viral latency protein, is required to inhibit the alpha interferon-induced antiviral response. J Virol 81:7844–7851

    Article  PubMed  CAS  Google Scholar 

  • Azarkh Y, Gilden D, Cohrs RJ (2010) Molecular characterization of varicella zoster virus in latently infected human ganglia: physical state and abundance of VZV DNA, quantitation of viral transcripts and detection of VZV-specific proteins. Curr Top Microbiol Immunol 342:229–241

    Article  PubMed  CAS  Google Scholar 

  • Cohen JI, Nguyen H (1998) Varicella-zoster virus ORF61 deletion mutants replicate in cell culture, but a mutant with stop codons in ORF61 reverts to wild-type virus. Virology 246:306–316

    Article  PubMed  CAS  Google Scholar 

  • Cohen JI, Sato H, Srinivas S, Lekstrom K (2001) Varicella-zoster virus (VZV) ORF65 virion protein is dispensable for replication in cell culture and is phosphorylated by casein kinase II, but not by the VZV protein kinases. Virology 280:62–71

    Article  PubMed  CAS  Google Scholar 

  • Cohen JI, Straus SE, Arvin AM (2007) Varicella-zoster virus replication, pathogenesis, and management. In: Knipe DM, Howley PM, Griffin DE, Lamb RA, Martin MA, Roizman B, Straus SE (eds) Fields virology. Lippincott Williams & Wilkins, Philadelphia, pp 2773–2818

    Google Scholar 

  • Cohrs RJ, Gilden DH (2007) Prevalence and abundance of latently transcribed varicella-zoster virus genes in human ganglia. J Virol 81:2950–2956

    Article  PubMed  CAS  Google Scholar 

  • Cohrs RJ, Barbour MB, Mahalingam R, Wellish M, Gilden DH (1995) Varicella-zoster virus (VZV) transcription during latency in human ganglia: prevalence of VZV gene 21 transcripts in latently infected human ganglia. J Virol 69:2674–2678

    PubMed  CAS  Google Scholar 

  • 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 70:2789–2796

    PubMed  CAS  Google Scholar 

  • 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 74:11464–11471

    Article  PubMed  CAS  Google Scholar 

  • Cohrs RJ, Gilden DH, Kinchington PR, Grinfeld E, Kennedy PG (2003a) Varicella-zoster virus gene 66 transcription and translation in latently infected human ganglia. J Virol 77:6660–6665

    Article  PubMed  CAS  Google Scholar 

  • Cohrs RJ, Hurley MP, Gilden DH (2003b) Array analysis of viral gene transcription during lytic infection of cells in tissue culture with varicella-zoster virus. J Virol 77:11718–11732

    Article  PubMed  CAS  Google Scholar 

  • Deitch SB, Gilden DH, Wellish M, Smith J, Cohrs RJ, Mahalingam R (2005) Array analysis of simian varicella virus gene transcription in productively infected cells in tissue culture. J Virol 79:5315–5325

    Article  PubMed  CAS  Google Scholar 

  • Eisfeld AJ, Turse SE, Jackson SA, Lerner EC, Kinchington PR (2006) Phosphorylation of the varicella-zoster virus (VZV) major transcriptional regulatory protein IE62 by the VZV open reading frame 66 protein kinase. J Virol 80:1710–1723

    Article  PubMed  CAS  Google Scholar 

  • Eisfeld AJ, Yee MB, Erazo A, Abendroth A, Kinchington PR (2007) Downregulation of class I major histocompatibility complex surface expression by varicella-zoster virus involves open reading frame 66 protein kinase-dependent and -independent mechanisms. J Virol 81:9034–9049

    Article  PubMed  CAS  Google Scholar 

  • Gray WL (2010) Simian varicella virus: molecular virology. Curr Top Microbiol Immunol 342:291–308

    Article  PubMed  CAS  Google Scholar 

  • Gray WL, Oakes JE (1984) Simian varicella virus DNA shares homology with human varicella-zoster virus DNA. Virology 136:241–246

    Article  PubMed  CAS  Google Scholar 

  • Gray WL, Starnes B, White MW, Mahalingam R (2001) The DNA sequence of the simian varicella virus genome. Virology 284:123–130

    Article  PubMed  CAS  Google Scholar 

  • Gray WL, Mullis L, Soike KF (2002) Viral gene expression during acute simian varicella virus infection. J Gen Virol 83:841–846

    PubMed  CAS  Google Scholar 

  • Gray WL, Davis K, Ou Y, Ashburn C, Ward TM (2007) Simian varicella virus gene 61 encodes a viral transactivator but is non-essential for in vitro replication. Arch Virol 152:553–563

    Article  PubMed  CAS  Google Scholar 

  • Grinfeld E, Kennedy PG (2007) The pattern of viral persistence in monkeys intra-tracheally infected with Simian varicella virus. Virus Genes 35:289–292

    Article  PubMed  CAS  Google Scholar 

  • Hood C, Cunningham AL, Slobedman B, Arvin AM, Sommer MH, Kinchington PR, Abendroth A (2006) Varicella-zoster virus ORF63 inhibits apoptosis of primary human neurons. J Virol 80:1025–1031

    Article  PubMed  CAS  Google Scholar 

  • Kaufer BB, Smejkal B, Osterrieder N (2010) The varicella-zoster virus ORFS/L (ORF0) gene is required for efficient viral replication and contains an element involved in DNA cleavage. J Virol 84:11661–11669

    Article  PubMed  CAS  Google Scholar 

  • Kemble GW, Annunziato P, Lungu O, Winter RE, Cha TA, Silverstein SJ, Spaete RR (2000) Open reading frame S/L of varicella-zoster virus encodes a cytoplasmic protein expressed in infected cells. J Virol 74:11311–11321

    Article  PubMed  CAS  Google Scholar 

  • Kennedy PG, Cohrs RJ (2010) Varicella-zoster virus human ganglionic latency: a current summary. J Neurovirol 16:411–418

    PubMed  Google Scholar 

  • Kennedy PG, Grinfeld E, Bell JE (2000) Varicella-zoster virus gene expression in latently infected and explanted human ganglia. J Virol 74:11893–11898

    Article  PubMed  CAS  Google Scholar 

  • Kennedy PG, Grinfeld E, Bontems S, Sadzot-Delvaux C (2001) Varicella-zoster virus gene expression in latently infected rat dorsal root ganglia. Virology 289:218–223

    Article  PubMed  CAS  Google Scholar 

  • Kennedy PG, Grinfeld E, Craigon M, Vierlinger K, Roy D, Forster T, Ghazal P (2005) Transcriptomal analysis of varicella-zoster virus infection using long oligonucleotide-based microarrays. J Gen Virol 86:2673–2684

    Article  PubMed  CAS  Google Scholar 

  • Kinchington PR, Fite K, Turse SE (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

    Article  PubMed  CAS  Google Scholar 

  • Litwin V, Jackson W, Grose C (1992) Receptor properties of two varicella-zoster virus glycoproteins, gpI and gpIV, homologous to herpes simplex virus gE and gI. J Virol 66:3643–3651

    PubMed  CAS  Google Scholar 

  • Mahalingam R, Smith D, Wellish M, Wolf W, Dueland AN, Cohrs R, Soike K, Gilden D (1991) Simian varicella virus DNA in dorsal root ganglia. Proc Natl Acad Sci USA 88:2750–2752

    Article  PubMed  CAS  Google Scholar 

  • Mallory S, Sommer M, Arvin AM (1997) Mutational analysis of the role of glycoprotein I in varicella-zoster virus replication and its effects on glycoprotein E conformation and trafficking. J Virol 71:8279–8288

    PubMed  CAS  Google Scholar 

  • Mallory S, Sommer M, Arvin AM (1998) Analysis of the glycoproteins I and E of varicella-zoster virus (VZV) using deletional mutations of VZV cosmids. J Infect Dis 178(Suppl 1):S22–S26

    Article  PubMed  CAS  Google Scholar 

  • McMillan DJ, Kay J, Mills JS (1997) Characterization of the proteinase specified by varicella-zoster virus gene 33. J Gen Virol 78(Pt 9):2153–2157

    PubMed  CAS  Google Scholar 

  • Messaoudi I, Barron A, Wellish M, Engelmann F, Legasse A, Planer S, Gilden D, Nikolich-Zugich J, Mahalingam R (2009) Simian varicella virus infection of rhesus macaques recapitulates essential features of varicella zoster virus infection in humans. PLoS Pathog 5:e1000657

    Article  PubMed  Google Scholar 

  • Moffat JF, Zerboni L, Sommer MH, Heineman TC, Cohen JI, Kaneshima H, Arvin AM (1998) The ORF47 and ORF66 putative protein kinases of varicella-zoster virus determine tropism for human T cells and skin in the SCID-hu mouse. Proc Natl Acad Sci USA 95:11969–11974

    Article  PubMed  CAS  Google Scholar 

  • Moriuchi H, Moriuchi M, Smith HA, Straus SE, Cohen JI (1992) Varicella-zoster virus open reading frame 61 protein is functionally homologous to herpes simplex virus type 1 ICP0. J Virol 66:7303–7308

    PubMed  CAS  Google Scholar 

  • Nagel MA, Gilden D, Shade T, Gao B, Cohrs RJ (2009) Rapid and sensitive detection of 68 unique varicella zoster virus gene transcripts in five multiplex reverse transcription-polymerase chain reactions. J Virol Methods 157:62–68

    Article  PubMed  CAS  Google Scholar 

  • 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 85:2276–2287

    Article  PubMed  CAS  Google Scholar 

  • Niizuma T, Zerboni L, Sommer MH, Ito H, Hinchliffe S, Arvin AM (2003) Construction of varicella-zoster virus recombinants from parent Oka cosmids and demonstration that ORF65 protein is dispensable for infection of human skin and T cells in the SCID-hu mouse model. J Virol 77:6062–6065

    Article  PubMed  CAS  Google Scholar 

  • Oliver SL, Sommer MH, Reichelt M, Rajamani J, Vlaycheva-Beisheim L, Stamatis S, Cheng J, Jones C, Zehnder J, Arvin AM (2011) Mutagenesis of varicella-zoster virus glycoprotein I (gI) identifies a cysteine residue critical for gE/gI heterodimer formation, gI structure, and virulence in skin cells. J Virol 85:4095–4110

    Article  PubMed  CAS  Google Scholar 

  • Ou Y, Davis KA, Traina-Dorge V, Gray WL (2007) Simian varicella virus expresses a latency-associated transcript that is antisense to open reading frame 61 (ICP0) mRNA in neural ganglia of latently infected monkeys. J Virol 81:8149–8156

    Article  PubMed  CAS  Google Scholar 

  • Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, Arbeit RD, Simberkoff MS, Gershon AA, Davis LE, Weinberg A, Boardman KD, Williams HM, Zhang JH, Peduzzi PN, Beisel CE, Morrison VA, Guatelli JC, Brooks PA, Kauffman CA, Pachucki CT, Neuzil KM, Betts RF, Wright PF, Griffin MR, Brunell P, Soto NE, Marques AR, Keay SK, Goodman RP, Cotton DJ, Gnann JW Jr, Loutit J, Holodniy M, Keitel WA, Crawford GE, Yeh SS, Lobo Z, Toney JF, Greenberg RN, Keller PM, Harbecke R, Hayward AR, Irwin MR, Kyriakides TC, Chan CY, Chan IS, Wang WW, Annunziato PW, Silber JL (2005) A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 352:2271–2284

    Article  PubMed  CAS  Google Scholar 

  • Pumphrey CY, Gray WL (1992) The genomes of simian varicella virus and varicella zoster virus are colinear. Virus Res 26:255–266

    Article  PubMed  CAS  Google Scholar 

  • Reichelt M, Brady J, Arvin AM (2009) The replication cycle of varicella-zoster virus: analysis of the kinetics of viral protein expression, genome synthesis, and virion assembly at the single-cell level. J Virol 83:3904–3918

    Article  PubMed  CAS  Google Scholar 

  • Ross J, Williams M, Cohen JI (1997) Disruption of the varicella-zoster virus dUTPase and the adjacent ORF9A gene results in impaired growth and reduced syncytia formation in vitro. Virology 234:186–195

    Article  PubMed  CAS  Google Scholar 

  • Sato H, Pesnicak L, Cohen JI (2003) 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

    Article  PubMed  CAS  Google Scholar 

  • Schaap A, Fortin JF, Sommer M, Zerboni L, Stamatis S, Ku CC, Nolan GP, Arvin AM (2005) T-cell tropism and the role of ORF66 protein in pathogenesis of varicella-zoster virus infection. J Virol 79:12921–12933

    Article  PubMed  CAS  Google Scholar 

  • Soike KF, Rangan SR, Gerone PJ (1984) Viral disease models in primates. Adv Vet Sci Comp Med 28:151–199

    PubMed  CAS  Google Scholar 

  • Sommer MH, Zagha E, Serrano OK, Ku CC, Zerboni L, Baiker A, Santos R, Spengler M, Lynch J, Grose C, Ruyechan W, Hay J, Arvin AM (2001) Mutational analysis of the repeated open reading frames, ORFs 63 and 70 and ORFs 64 and 69, of varicella-zoster virus. J Virol 75:8224–8239

    Article  PubMed  CAS  Google Scholar 

  • Soong W, Schultz JC, Patera AC, Sommer MH, Cohen JI (2000) Infection of human T lymphocytes with varicella-zoster virus: an analysis with viral mutants and clinical isolates. J Virol 74:1864–1870

    Article  PubMed  CAS  Google Scholar 

  • Streblow DN, van Cleef KW, Kreklywich CN, Meyer C, Smith P, Defilippis V, Grey F, Fruh K, Searles R, Bruggeman C, Vink C, Nelson JA, Orloff SL (2007) Rat cytomegalovirus gene expression in cardiac allograft recipients is tissue specific and does not parallel the profiles detected in vitro. J Virol 81:3816–3826

    Article  PubMed  CAS  Google Scholar 

  • Xia D, Srinivas S, Sato H, Pesnicak L, Straus SE, Cohen JI (2003) Varicella-zoster virus open reading frame 21, which is expressed during latency, is essential for virus replication but dispensable for establishment of latency. J Virol 77:1211–1218

    Article  PubMed  CAS  Google Scholar 

  • Zerboni L, Berarducci B, Rajamani J, Jones CD, Zehnder JL, Arvin A (2011) Varicella-zoster virus glycoprotein E is a critical determinant of virulence in the SCID mouse-human model of neuropathogenesis. J Virol 85:98–111

    Article  PubMed  CAS  Google Scholar 

  • Zhang Z, Selariu A, Warden C, Huang G, Huang Y, Zaccheus O, Cheng T, Xia N, Zhu H (2010) Genome-wide mutagenesis reveals that ORF7 is a novel VZV skin-tropic factor. PLoS Pathog 6:e1000971

    Article  PubMed  Google Scholar 

  • Zhu L, Weller SK (1988) UL5, a protein required for HSV DNA synthesis: genetic analysis, overexpression in Escherichia coli, and generation of polyclonal antibodies. Virology 166:366–378

    Article  PubMed  CAS  Google Scholar 

  • Zhu LA, Weller SK (1992) The six conserved helicase motifs of the UL5 gene product, a component of the herpes simplex virus type 1 helicase-primase, are essential for its function. J Virol 66:469–479

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank Anj Stadnik and Kyung Park for technical assistance; the Division of Animal Resources (DAR) at the Oregon National Primate Research Center for expert animal care, especially Drs. Anne Lewis and Lois Colgin for conducting the necropsies and collecting tissues; and Alfred Legasse, Miranda Fischer, and Jesse Dewayne for collection of blood and BAL samples. This work was supported by the American Heart Association career development grant 0930234N, NIH R01AG037042, 2T32AI007472-16, NIH P51 RR00163-51, and the Brookdale Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ilhem Messaoudi.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Table 1

(JPEG 11929 kb)

High resolution image (EPS 718 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Meyer, C., Kerns, A., Barron, A. et al. Simian varicella virus gene expression during acute and latent infection of rhesus macaques. J. Neurovirol. 17, 600–612 (2011). https://doi.org/10.1007/s13365-011-0057-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13365-011-0057-y

Keywords

Navigation