Journal of NeuroVirology

, Volume 22, Issue 5, pp 555–563 | Cite as

Overexpression of thyroid hormone receptor β1 altered thyroid hormone-mediated regulation of herpes simplex virus-1 replication in differentiated cells

  • Feng Chen
  • Robert W. Figliozzi
  • Gautam Bedadala
  • Jayavardhana Palem
  • S. Victor HsiaEmail author


Thyroid hormone (T3) has been suggested to play a role in herpes simplex virus 1 (HSV-1) replication. It was previously reported that HSV-1 replication was suppressed by T3 in mouse neuroblastoma cells overexpressing thyroid hormone receptor β1 (TRβ1). Using a human neuro-endocrine cells LNCaP differentiated by androgen deprivation, HSV-1 replication was active but decreased by T3 at very low moi, probably due to low copy of TRβ1. In this study, a recombinant HSV-1 was constructed expressing TRβ1 (HSV-1/TRβ1). Infection of Vero cells (very little TRβ1 expression) with HSV-1/TRβ1 exhibited increased replication in the presence of T3 compared to the counterpart without TRβ1 overexpression. Interestingly, HSV-1/TRβ1 infection of differentiated LNCaP cells showed strong suppression of viral replication by T3 and the removal of hormone did not fully reversed the suppression as was observed in parent virus. Quantitative analyses indicated that ICP0 expression was blocked using HSV-1/TRβ1 for infection during T3 washout, suggesting that overexpression of TRβ1 is likely to delay its inhibitory effect on viral gene expression. Together these results emphasized the importance of TRβ1 in the regulation of HSV-1 replication in differentiated environment with neuronal phenotype.


Herpes simplex virus Thyroid hormone Differentiation Neurons Plaque assay Thyroid hormone receptor beta 1 



Herpes simplex virus type-1


Thyroid hormone


Quantitative polymerase chain reaction


Quantitative reverse transcription polymerase chain reaction


Multiplicity of infection


Green fluorescent protein




Peptidylprolyl isomerase A


Days post infection




Thyroid hormone receptor beta 1


Thyroid hormone receptor element





This project is supported by R01NS081109 to SVH from NIH and the content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS/NIH. The authors appreciate the assistance of the editorial staff at UMES.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.


  1. Ajavon, A., et al. (2015). Influence of thyroid hormone disruption on the incidence of shingles. Epidemiol Infect 143(16):3557–3571.Google Scholar
  2. Amelio AL, McAnany PK, Bloom DC (2006) A chromatin insulator-like element in the herpes simplex virus type 1 latency-associated transcript region binds CCCTC-binding factor and displays enhancer-blocking and silencing activities. J Virol 80(5):2358–68CrossRefPubMedPubMedCentralGoogle Scholar
  3. Bedadala GR, Pinnoji RC, Hsia SC (2007) Early growth response gene 1 (Egr-1) regulates HSV-1 ICP4 and ICP22 gene expression. Cell Res 17(5):1–10Google Scholar
  4. Bedadala GR et al (2010) Thyroid hormone controls the gene expression of HSV-1 LAT and ICP0 in neuronal cells. Cell Res 20(5):587–98CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bedadala G et al (2014) Construction and characterization of recombinant HSV-1 expressing early growth response-1. ISRN Virol 2014Google Scholar
  6. Block T et al (1994) Long term herpes simplex virus type 1 infection of nerve growth factor-treated PC12 cells. J Gen Virol 75(Pt 9):2481–7CrossRefPubMedGoogle Scholar
  7. Bloom DC (2004) HSV LAT and neuronal survival. Int Rev Immunol 23(1–2):187–98CrossRefPubMedGoogle Scholar
  8. Branco FJ, Fraser NW (2005) Herpes simplex virus type 1 latency-associated transcript expression protects trigeminal ganglion neurons from apoptosis. J Virol 79(14):9019–25CrossRefPubMedPubMedCentralGoogle Scholar
  9. Bystricka M, Russ G (2005) Immunity in latent herpes simplex virus infection. Acta Virol 49(3):159–67PubMedGoogle Scholar
  10. Carpenter D et al (2007) 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 369(1):12–8CrossRefPubMedPubMedCentralGoogle Scholar
  11. Chen, Q et al. (2007) CTCF-dependent chromatin boundary element exists between the LAT and ICP0 promoters in the HSV-1 genome. J Virol 81(10):5192–5201Google Scholar
  12. Chen F, et al. (2014) A novel thyroid hormone mediated regulation of HSV-1 gene expression and replication is specific to neuronal cells and associated with disruption of chromatin condensation. SOJ Pharm Pharm Sci 1(1). pii:06Google Scholar
  13. Cui C et al (2006) Prediction and identification of herpes simplex virus 1-encoded microRNAs. J Virol 80(11):5499–508CrossRefPubMedPubMedCentralGoogle Scholar
  14. Figliozzi RW et al (2014) Thyroid hormone-dependent epigenetic suppression of herpes simplex virus-1 gene expression and viral replication in differentiated neuroendocrine cells. J Neurol Sci 346(1–2):164–73CrossRefPubMedPubMedCentralGoogle Scholar
  15. Foster TP, Rybachuk GV, Kousoulas KG (1998) Expression of the enhanced green fluorescent protein by herpes simplex virus type 1 (HSV-1) as an in vitro or in vivo marker for virus entry and replication. J Virol Methods 75(2):151–60CrossRefPubMedGoogle Scholar
  16. Garza HH Jr, Hill JM (1997) Effect of a beta-adrenergic antagonist, propranolol, on induced HSV-1 ocular recurrence in latently infected rabbits. Curr Eye Res 16(5):453–8CrossRefPubMedGoogle Scholar
  17. Glauser L, Barakat Walter I (1997) Differential distribution of thyroid hormone receptor isoform in rat dorsal root ganglia and sciatic nerve in vivo and in vitro. J Neuroendocrinol 9(3):217–27CrossRefPubMedGoogle Scholar
  18. Grontved L et al (2015) Transcriptional activation by the thyroid hormone receptor through ligand-dependent receptor recruitment and chromatin remodelling. Nat Commun 6:7048CrossRefPubMedGoogle Scholar
  19. Hardwicke MA, Schaffer PA (1997) Differential effects of nerve growth factor and dexamethasone on herpes simplex virus type 1 oriL- and oriS-dependent DNA replication in PC12 cells. J Virol 71(5):3580–7PubMedPubMedCentralGoogle Scholar
  20. Hodin RA et al (1989) Identification of a thyroid hormone receptor that is pituitary-specific. Science 244(4900):76–9CrossRefPubMedGoogle Scholar
  21. Hodin RA, Lazar MA, Chin WW (1990) Differential and tissue-specific regulation of the multiple rat c-erbA messenger RNA species by thyroid hormone. J Clin Invest 85(1):101–5CrossRefPubMedPubMedCentralGoogle Scholar
  22. Hsia SH, Hsia SV (2014) A cohort historical analysis of the relationship between thyroid hormone malady and alpha-human herpesvirus activation. J Steroids Horm Sci 5(2):133PubMedPubMedCentralGoogle Scholar
  23. Hsia SC et al (2010) Regulation of herpes simplex virus type 1 thymidine kinase gene expression by thyroid hormone receptor in cultured neuronal cells. J Neurovirol 16(1):13–24CrossRefPubMedPubMedCentralGoogle Scholar
  24. Hsia SC, Bedadala GR, Balish MD (2011) Effects of thyroid hormone on HSV-1 gene regulation: implications in the control of viral latency and reactivation. Cell Biosci 1(1):24CrossRefPubMedPubMedCentralGoogle Scholar
  25. Knipe DM, Cliffe A (2008) Chromatin control of herpes simplex virus lytic and latent infection. Nat Rev Microbiol 6(3):211–21CrossRefPubMedGoogle Scholar
  26. Knipe DM, Howley PM (2013) Fields virology, 6th edn. Wolters Kluwer/Lippincott Williams & Wilkins Health, Philadelphia, PA, 2 volumesGoogle Scholar
  27. Koelle DM, Corey L (2008) Herpes simplex: insights on pathogenesis and possible vaccines. Annu Rev Med 59:381–395CrossRefPubMedGoogle Scholar
  28. Kubat NJ et al (2004a) The herpes simplex virus type 1 latency-associated transcript (LAT) enhancer/rcr is hyperacetylated during latency independently of LAT transcription. J Virol 78(22):12508–18CrossRefPubMedPubMedCentralGoogle Scholar
  29. Kubat NJ et al (2004b) Specific histone tail modification and not DNA methylation is a determinant of herpes simplex virus type 1 latent gene expression. J Virol 78(3):1139–49CrossRefPubMedPubMedCentralGoogle Scholar
  30. Lazar MA (1993) Thyroid hormone receptors: multiple forms, multiple possibilities. Endocr Rev 14(2):184–93PubMedGoogle Scholar
  31. Lebel JM, Dussault JH, Puymirat J (1994) Overexpression of the beta 1 thyroid receptor induces differentiation in neuro-2a cells. Proc Natl Acad Sci U S A 91(7):2644–8CrossRefPubMedPubMedCentralGoogle Scholar
  32. Marquart M et al (2003) Ocular reactivation phenotype of HSV-1 strain F(MP)E, a corticosteroid-sensitive strain. Curr Eye Res 26(3–4):205–9CrossRefPubMedGoogle Scholar
  33. Mehta A et al (1995) In situ DNA PCR and RNA hybridization detection of herpes simplex virus sequences in trigeminal ganglia of latently infected mice. Virology 206(1):633–40CrossRefPubMedGoogle Scholar
  34. Moxley MJ et al (2002) Herpes simplex virus type 1 infection prevents detachment of nerve growth factor-differentiated PC12 cells in culture. J Gen Virol 83(Pt 7):1591–600CrossRefPubMedGoogle Scholar
  35. Noisakran S et al (1998) Role of the hypothalamic pituitary adrenal axis and IL-6 in stress-induced reactivation of latent herpes simplex virus type 1. J Immunol 160(11):5441–7PubMedGoogle Scholar
  36. Oppenheimer JH, Schwartz HL (1997) Molecular basis of thyroid hormone-dependent brain development. Endocr Rev 18(4):462–75PubMedGoogle Scholar
  37. Peng W et al (2004) Mapping herpes simplex virus type 1 latency-associated transcript sequences that protect from apoptosis mediated by a plasmid expressing caspase-8. J Neurovirol 10(4):260–5CrossRefPubMedGoogle Scholar
  38. Perng GC et al (2000) Virus-induced neuronal apoptosis blocked by the herpes simplex virus latency-associated transcript. Science 287(5457):1500–3CrossRefPubMedGoogle Scholar
  39. Pinnoji RC et al (2007) Repressor element-1 silencing transcription factor/neuronal restrictive silencer factor (REST/NRSF) can regulate HSV-1 immediate-early transcription via histone modification. Virol J 4:56CrossRefPubMedPubMedCentralGoogle Scholar
  40. Su YH et al (2000) The HSV 1 genome in quiescently infected NGF differentiated PC12 cells can not be stimulated by HSV superinfection. J Neurovirol 6(4):341–9CrossRefPubMedGoogle Scholar
  41. Su YH et al (2002) Stability and circularization of herpes simplex virus type 1 genomes in quiescently infected PC12 cultures. J Gen Virol 83(Pt 12):2943–50CrossRefPubMedGoogle Scholar
  42. Umbach JL et al (2008) MicroRNAs expressed by herpes simplex virus 1 during latent infection regulate viral mRNAs. Nature 454(7205):780–3PubMedPubMedCentralGoogle Scholar
  43. Varedi M et al (2014) Effects of hypo- and hyperthyroid states on herpes simplex virus infectivity in the rat. Endocr Res 39(2):50–5CrossRefPubMedGoogle Scholar
  44. Wang K et al (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(22):14079–87CrossRefPubMedPubMedCentralGoogle Scholar
  45. Watson S et al (2007) Determination of suitable housekeeping genes for normalisation of quantitative real time PCR analysis of cells infected with human immunodeficiency virus and herpes viruses. Virol J 4:130CrossRefPubMedPubMedCentralGoogle Scholar
  46. Wrange O, Carlstedt-Duke J, Gustafsson JA (1979) Purification of the glucocorticoid receptor from rat liver cytosol. J Biol Chem 254(18):9284–90PubMedGoogle Scholar
  47. Yang L, Voytek CC, Margolis TP (2000) Immunohistochemical analysis of primary sensory neurons latently infected with herpes simplex virus type 1. J Virol 74(1):209–17CrossRefPubMedPubMedCentralGoogle Scholar
  48. Yen PM (2001) Physiological and molecular basis of thyroid hormone action. Physiol Rev 81(3):1097–142PubMedGoogle Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2016

Authors and Affiliations

  • Feng Chen
    • 1
  • Robert W. Figliozzi
    • 1
    • 2
  • Gautam Bedadala
    • 1
    • 3
  • Jayavardhana Palem
    • 3
  • S. Victor Hsia
    • 1
    • 2
    Email author
  1. 1.Department of Pharmaceutical Sciences, School of Pharmacy and Health ProfessionsUniversity of Maryland Eastern ShorePrincess AnneUSA
  2. 2.Department of Natural Sciences, School of Agriculture and Natural SciencesUniversity of Maryland Eastern ShorePrincess AnneUSA
  3. 3.Department of Basic Pharmaceutical Sciences, College of PharmacyUniversity of Louisiana MonroeMonroeUSA

Personalised recommendations