Skip to main content
NCBI home page
Springer Nature - PMC COVID-19 Collection logoLink to Springer Nature - PMC COVID-19 Collection
. 2007;13(6):569–578. doi: 10.1080/13550280701620754

Identification of a novel protein encoded by the latency-related gene of bovine herpesvirus 1

Florencia Meyer 1,2, Sandra Perez 3,1,4, Yunquan Jiang 3,1, You Zhou 3,1, Gail Henderson 3,1, Clinton Jones 3,1,✉
PMCID: PMC7095411  PMID: 18097888

Abstract

The latency-related (LR) RNA encoded by bovine herpesvirus 1 (BHV-1) is abundantly expressed and alternatively spliced in trigeminal ganglia. A mutant BHV-1 strain that contains three stop codons at the beginning of LR open reading frame (ORF)-2 (LR mutant virus) does not express ORF-2 or an adjacent reading frame that lacks an initiating ATG (RF-C). Calves latently infected with wild-type (wt) BHV-1, but not with the LR mutant virus, reactivate from latency, indicating that proteins encoded by the LR gene regulate the latency-reactivation cycle. The LR gene also contains another large ORF (ORF-1) that is approximately 200 bp downstream of stop codons inserted at the N-terminus of ORF-2. To test whether the LR mutant virus can expresses ORF-1, the authors developed antiserum directed against ORF-1. The ORF-1 antiserum recognizes specific proteins in bovine cells productively infected with wt BHV-1. ORF-1 protein expression is reduced, but not blocked, when bovine cells are infected with the LR mutant virus. Confocal microscopy demonstrated ORF-1 is present in the cytoplasm and nucleus of productively infected cells, whereas RF-C or a fusion protein containing RF-C localizes to the cytoplasm. Trigeminal ganglia from calves latently infected with wt BHV-1 contain neurons specifically stained with the ORF-1 antiserum. These studies suggest ORF-1 expression may be important for the BHV-1 latency-reactivation cycle.

Keywords: bovine herpesvirus type 1, latency-related gene

Footnotes

This work was supported by two USDA grants (2005-01554 and 2006-01627), and, in part, a Public Health Service grant, 1P20RR15635, to the Nebraska Center for Virology.

References

  1. Bowland SL, Shewen PE. Bovine respiratory disease: commercial vaccines currently available in Canada. Can Vet J. 2000;41:33–48. [PMC free article] [PubMed] [Google Scholar]
  2. Bratanich AC, Hanson ND, Jones CJ. The latency-related gene of bovine herpesvirus 1 inhibits the activity of immediate-early transcription unit 1. Virology. 1992;191:988–991. doi: 10.1016/0042-6822(92)90278-W. [DOI] [PubMed] [Google Scholar]
  3. Carter JJ, Weinberg AD, Pollard A, Reeves R, Magnuson JA, Magnuson NS. Inhibition of T-lymphocyte mitogenic responses and effects on cell functions by bovine herpesvirus 1. J Virol. 1989;63:1525–1530. doi: 10.1128/jvi.63.4.1525-1530.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Ciacci-Zanella J, Stone M, Henderson G, Jones C. The latency-related gene of bovine herpesvirus 1 inhibits programmed cell death. J Virol. 1999;73:9734–9740. doi: 10.1128/jvi.73.12.9734-9740.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Delmas V, Stokes DG, Perry RP. A mammalian DNA-binding protein that contains a chromodomain and an SNF2/SW12-like helicase domain. Proc Nat Acad Sci U S A. 1993;90:2414–2418. doi: 10.1073/pnas.90.6.2414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Devireddy LR, Jones C. Alternative splicing of the latency-related transcript of bovine herpesvirus 1 yields RNAs containing unique open reading frames. J Virol. 1998;72:7294–7301. doi: 10.1128/jvi.72.9.7294-7301.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Devireddy L, Zhang Y, Jones C. Cloning and initial characterization of an alternatively spliced transcript encoded by the bovine herpes virus 1 latency related (LR) gene. J NeuroVirol. 2003;9:612–622. doi: 10.1080/13550280390247542. [DOI] [PubMed] [Google Scholar]
  8. Geiser V, Inman M, Zhang Y, Jones C. The latency related (LR) gene of bovine herpes virus 1 (BHV-1) can inhibit the ability of bICP0 to activate productive infection. J Gen Virol. 2002;83:2965–2971. doi: 10.1099/0022-1317-83-12-2965. [DOI] [PubMed] [Google Scholar]
  9. Geiser V, Jones C. The latency related gene encoded by bovine herpesvirus 1 encodes a small regulatory RNA that inhibits cell growth. J NeuroVirol. 2005;11:563–570. doi: 10.1080/13550280500385286. [DOI] [PubMed] [Google Scholar]
  10. Griebel PJ, Ohmann HB, Lawman MJ, Babiuk LA. The interaction between bovine herpesvirus type 1 and activated bovine T lymphocytes. J Gen Virol. 1990;71:369–377. doi: 10.1099/0022-1317-71-2-369. [DOI] [PubMed] [Google Scholar]
  11. Griebel PJ, Qualtiere L, Davis WC, Gee A, Bielefeldt Ohmann H, Lawman MJ, Babiuk LA. T lymphocyte population dynamics and function following a primary bovine herpesvirus type-1 infection. Viral Immunol. 1987;1:287–304. doi: 10.1089/vim.1987.1.287. [DOI] [PubMed] [Google Scholar]
  12. Griebel PJ, Qualtiere L, Davis WC, Lawman MJ, Babiuk LA. Bovine peripheral blood leukocyte subpopulation dynamics following a primary bovine herpesvirus-1 infection. Viral Immunol. 1987;1:267–286. doi: 10.1089/vim.1987.1.267. [DOI] [PubMed] [Google Scholar]
  13. Gussow AM, Giordani NC, Tran RK, Imai Y, Kwiatkowski DL, Rall GF, Margolis TP, Bloom DC. Tissue-specific splicing of the herpes simplex virus type 1 latency-associated transcript (LAT) intron in LAT transgenic mice. J Virol. 2006;80:9414–9423. doi: 10.1128/JVI.00530-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hossain A, Schang LM, Jones C. Identification of gene products encoded by the latency-related gene of bovine herpesvirus 1. J Virol. 1995;69:5345–5352. doi: 10.1128/jvi.69.9.5345-5352.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Inman M, Lovato L, Doster A, Jones C. A mutation in the latency-related gene of bovine herpesvirus 1 leads to impaired ocular shedding in acutely infected calves. J Virol. 2001;75:8507–8515. doi: 10.1128/JVI.75.18.8507-8515.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Inman M, Lovato L, Doster A, Jones C. A mutation in the latency related gene of bovine herpesvirus 1 interferes with the latency-reactivation cycle of latency in calves. J Virol. 2002;76:6771–6779. doi: 10.1128/JVI.76.13.6771-6779.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Inman M, Zhou J, Webb H, Jones C. Identification of a novel transcript containing a small open reading frame that is expressed during latency, and is antisense to the latency related gene of bovine herpes virus 1 (BHV-1) J Virol. 2004;78:5438–5447. doi: 10.1128/JVI.78.10.5438-5447.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ishmael W (2001). Gasping for dollars. Angus Beef Bulletin wwwmycattlecom/health/updates/gaspingfordollars.
  19. Jiang Y, Hossain A, Winkler MT, Holt T, Doster A, Jones C. A protein encoded by the latency-related gene of bovine herpesvirus 1 is expressed in trigeminal ganglionic neurons of latently infected cattle and interacts with cyclin-dependent kinase 2 during productive infection. J Virol. 1998;72:8133–8142. doi: 10.1128/jvi.72.10.8133-8142.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Jiang Y, Inman M, Zhang Y, Posadas NA, Jones C. A mutation in the latency related gene of bovine herpesvirus 1 (BHV-1) inhibits protein expression of a protein from open reading frame 2 (ORF-2) and an adjacent reading frame during productive infection. J Virol. 2004;78:3184–3189. doi: 10.1128/JVI.78.6.3184-3189.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Jones C. Alphaherpesvirus latency: its role in disease and survival of the virus in nature. Adv Virus Res. 1998;51:81–133. doi: 10.1016/S0065-3527(08)60784-8. [DOI] [PubMed] [Google Scholar]
  22. Jones C. Herpes simplex virus type 1 and bovine herpesvirus 1 latency. Clin Micro Rev. 2003;16:79–95. doi: 10.1128/CMR.16.1.79-95.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kapil S, Basaraba RJ. Infectious bovine rhinotracheitis, parainfluenza-3, and respiratory coronavirus. Bovine respiratory disease update. Vet Clin N Am Food Anim Pract. 1997;13:455–461. doi: 10.1016/S0749-0720(15)30308-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Knosp WM, Scott V, Bachinger HP, Stadler HS. HOXA13 regulates the expression of bone morphogenetic proteins 2 and 7 to control distal limb morphogenesis. Development. 2004;131:4581–4592. doi: 10.1242/dev.01327. [DOI] [PubMed] [Google Scholar]
  25. Koppers-Lalic EA, Reits EAJ, Ressing ME, Lipinska AD, Abele R, Koch J, Rezende MM, Admiraal P, van Leeuwen D, Bienkowsaka-Szewczyc K, Mettenleiter TC, Rijsewijk FAM, Tampe R, Neefjes J, Wiertz EJ. Varicelloviruses avoid T cell recognition by UL49.5-mediated inactivation of the transporter associated with antigen processing. Proc Natl Acad Sci U S A. 2005;102:5144–5149. doi: 10.1073/pnas.0501463102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kutish G, Mainprize T, Rock D. Characterization of the latency-related transcriptionally active region of the bovine herpesvirus 1 genome. J Virol. 1990;64:5730–5737. doi: 10.1128/jvi.64.12.5730-5737.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lovato L, Inman M, Henderson G, Doster A, Jones C. Infection of cattle with a bovine herpesvirus 1 (BHV-1) strain that contains a mutation in the latency related gene leads to increased apoptosis in trigeminal ganglia during the transition from acute infection to latency. J Virol. 2003;77:4848–4857. doi: 10.1128/JVI.77.8.4848-4857.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Meyer F, Perez S, Geiser V, Sintek M, Inman M, Jones C. A protein encoded by the bovine herpes virus 1 (BHV-1) latency related gene interacts with specific cellular regulatory proteins, including the CCAAT enhancer binding protein alpha(C/EBP-a) J Virol. 2007;81:59–67. doi: 10.1128/JVI.01171-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Mott K, Osorio N, Jin L, Brick D, Naito J, Cooper J, Henderson G, Inman M, Jones C, Wechsler SL, Perng G-C. The bovine herpesvirus 1 LR ORF2 is crucial for this gene’s ability to restore the high reactivation phenotype to a Herpes simplex virus-1 LAT null mutant. J Gen Virol. 2003;84:2975–2985. doi: 10.1099/vir.0.19421-0. [DOI] [PubMed] [Google Scholar]
  30. Perez S, Inman M, Doster A, Jones C. Latency-realated gene encoded by bovine herpesvirus 1 promotes virus growth and reactivation from latency in tonsils of infected calves. J Clin Micro. 2005;43:393–401. doi: 10.1128/JCM.43.1.393-401.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Perez S, Lovato L, Zhou J, Doster A, Jones C. Comparison of inflammatory infiltrates in trigeminal ganglia of cattle infected with wild type BHV-1 versus a virus strain containing a mutaition in the LR (latency-related) gene. J NeuroVirol. 2006;12:392–397. doi: 10.1080/13550280600936459. [DOI] [PubMed] [Google Scholar]
  32. Perng G-C, Maguen B, Jin L, Mott KR, Osorio N, Slanina SM, Yukht A, Ghiasi H, Nesburn AB, Inman M, Henderson G, Jones C, Wechsler SL. A gene capable of blocking apoptosis can substitute for the herpes simplex virus type 1 latency-associated transcript gene and restore wild-type reactivation levels. J Virol. 2002;76:1224–1235. doi: 10.1128/JVI.76.3.1224-1235.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Powell J (2005). Bovine respiratory disease. University of Arkansas Division of Agriculture Cooperative Extension Service FSA: 3082.
  34. Rock DL, Beam SL, Mayfield JE. Mapping bovine herpesvirus type 1 latency-related RNA in trigeminal ganglia of latently infected rabbits. J Virol. 1987;61:3827–31. doi: 10.1128/jvi.61.12.3827-3831.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Rock D, Lokensgard J, Lewis T, Kutish G. Characterization of dexamethasone-induced reactivation of latent bovine herpesvirus 1. J Virol. 1992;66:2484–2490. doi: 10.1128/jvi.66.4.2484-2490.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Schang LM, Hossain A, Jones C. The latency-related gene of bovine herpesvirus 1 encodes a product which inhibits cell cycle progression. J Virol. 1996;70:3807–3814. doi: 10.1128/jvi.70.6.3807-3814.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Schang LM, Jones C. Analysis of bovine herpesvirus 1 transcripts during a primary infection of trigeminal ganglia of cattle. J Virol. 1997;71:6786–6795. doi: 10.1128/jvi.71.9.6786-6795.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Scoumanne A, Cheng X. The lysine-specific demethylase 1 is required for cell proliferation in both p53-dependent and -independent manners. J Biol Chem. 2007;282:15471–15475. doi: 10.1074/jbc.M701023200. [DOI] [PubMed] [Google Scholar]
  39. Sheffy BE, Davies DH. Reactivation of a bovine herpesvirus after corticosteroid treatment. Proc Soc Exp Biol Med. 1972;140:974–976. doi: 10.3181/00379727-140-36592. [DOI] [PubMed] [Google Scholar]
  40. Tikoo SK, Campos M, Babiuk LA. Bovine herpesvirus 1 (BHV-1): biology, pathogenesis, and control. Adv Virus Res. 1995;45:191–223. doi: 10.1016/S0065-3527(08)60061-5. [DOI] [PubMed] [Google Scholar]
  41. Weaver T, White R. Headcase, an imaginal specific gene required for adult morphogenesis in Drosophila melanogaster. Development. 1995;121:4149–4160. doi: 10.1242/dev.121.12.4149. [DOI] [PubMed] [Google Scholar]
  42. Winkler MT, Doster A, Jones C. Bovine herpesvirus 1 can infect CD4(+) T lymphocytes and induce programmed cell death during acute infection of cattle. J Virol. 1999;73:8657–8668. doi: 10.1128/jvi.73.10.8657-8668.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Winkler MT, Doster A, Sur JH, Jones C. Analysis of bovine trigeminal ganglia following infection with bovine herpesvirus 1. Vet Microbiol. 2002;86:139–155. doi: 10.1016/S0378-1135(01)00498-9. [DOI] [PubMed] [Google Scholar]
  44. Winkler MT, Schang LS, Doster A, Holt T, Jones C. Analysis of cyclins in trigeminal ganglia of calves infected with bovine herpesvirus-1. J Gen Virol. 2000;81:2993–2998. doi: 10.1099/0022-1317-81-12-2993. [DOI] [PubMed] [Google Scholar]
  45. Winkler MTC, Doster A, Jones C. Persistence and reactivation of bovine herpesvirus 1 in the tonsil of latently infected calves. J Virol. 2000;74:5337–5346. doi: 10.1128/JVI.74.11.5337-5346.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Neurovirology are provided here courtesy of Nature Publishing Group

RESOURCES