Skip to main content
NCBI home page
Virologica Sinica logoLink to Virologica Sinica
. 2014 Oct 22;29(5):274–283. doi: 10.1007/s12250-014-3495-x

Role of the virion host shutoff protein in neurovirulence of monkey B virus (Macacine herpesvirus 1)

Darla Black 1, Jerry Ritchey 1, Mark Payton 2, Richard Eberle 1,✉
PMCID: PMC5896283  NIHMSID: NIHMS955426  PMID: 25341947

Abstract

Monkey B virus (Macacine herpesvirus 1; BV) is noted for its extreme neurovirulence in humans. Since the vhs protein encoded by the UL41 gene has been shown to be a neurovirulence factor in the related human herpes simplex viruses, the role of the UL41 gene in BV neurovirulence was investigated. BV mutants were constructed that lacked the entire UL41 ORF (Δ41) or had the RNase active site mutated (Δ41A). Neither mutant shut off host protein synthesis, degraded β-actin mRNA, or prevented an IFN-β response, indicating that the vhs protein and its RNase activity are both necessary for these activities. Replication of both mutants in primary mouse cells was impaired and they exhibited a prolonged disease course in mice. Whereas Δ41 infected mice were euthanized for symptoms related to central nervous system (CNS) infection, Δ41A infected mice were euthanized primarily for symptoms of autonomic nervous system dysfunction. While neuroinvasiveness was not affected, lesions in the CNS were more limited in size, anatomical distribution, and severity than for wild-type virus. These results indicate that the vhs protein affects the general replicative efficiency of BV in vivo rather than being a specific neurovirulence factor critical for invasion of or preferential replication in the CNS.

Keywords: herpesvirus, monkey B virus, UL41, virion host shutoff, neurovirulence

References

  1. Barzilai A, Zivony-Elbom I, Sarid R, Noah E, Frenkel N. The herpes simplex virus type 1 vhs-UL41 gene secures viral replication by temporarily evading apoptotic cellular response to infection: Vhs-UL41 activity might require interactions with elements of cellular mRNA degradation machinery. J Virol. 2006;80:505–513. doi: 10.1128/JVI.80.1.505-513.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Black D H, Saliki J T, Eberle R. Development of a green fluorescent protein reporter cell line to reduce biohazards associated with detection of infectious Cercopithecine herpesvirus 1 (monkey B virus) in clinical specimens. Compar Med. 2002;52:534–542. [PubMed] [Google Scholar]
  3. Chou J, Kern E R, Whitley R J, Roizman B. Mapping of herpes simplex virus-1 neurovirulence to gamma 134.5, a gene nonessential for growth in culture. Science. 1990;250:1262–1266. doi: 10.1126/science.2173860. [DOI] [PubMed] [Google Scholar]
  4. Dauber B, Pelletier J, Smiley J R. The herpes simplex virus 1 vhs protein enhances translation of viral true late mRNAs and virus production in a cell type-dependent manner. J Virol. 2011;85:5363–5373. doi: 10.1128/JVI.00115-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Duerst R J, Morrison L A. Herpes simplex virus 2 virion host shutoff protein interferes with type I interferon production and responsiveness. Virology. 2004;322:158–167. doi: 10.1016/j.virol.2004.01.019. [DOI] [PubMed] [Google Scholar]
  6. Elmore D, Eberle R. Monkey B virus (Cercopithecine herpesvirus 1) Compar Med. 2008;58:11–21. [PMC free article] [PubMed] [Google Scholar]
  7. Esclatine A, Taddeo B, Evans L, Roizman B. The herpes simplex virus 1 UL41 gene-dependent destabilization of cellular RNAs is selective and may be sequence-specific. Proc Natl Acad Sci U S A. 2004;101:3603–3608. doi: 10.1073/pnas.0400354101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Esclatine A, Taddeo B, Roizman B. The UL41 protein of herpes simplex virus mediates selective stabilization or degradation of cellular mRNAs. Proc Natl Acad Sci U S A. 2004;101:18165–18170. doi: 10.1073/pnas.0408272102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Everly D N, Feng P, Mian I S, Read G S. mRNA degradation by the virion host shutoff (vhs) protein of herpes simplex virus: genetic and biochemical evidence that vhs is a nuclease. J Virol. 2002;76:8560–8571. doi: 10.1128/JVI.76.17.8560-8571.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Feng P, Everly D N, Jr., Read G S. mRNA decay during herpes simplex virus (HSV) infections: protein-protein interactions involving the HSV virion host shutoff protein and translation factors eIF4H and eIF4A. J Virol. 2005;79:9651–9664. doi: 10.1128/JVI.79.15.9651-9664.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hilliard J K, Eberle R, Lipper S L, Munoz R M, Weiss S A. Herpesvirus simiae (B virus): replication of the virus and identification of viral polypeptides in infected cells. Arch Virol. 1987;93:185–198. doi: 10.1007/BF01310973. [DOI] [PubMed] [Google Scholar]
  12. Huff J L, Barry P A. B-virus (Cercopithecine herpesvirus 1) infection in humans and macaques: potential for zoonotic disease. Emer Infect Dis. 2003;9:246–250. doi: 10.3201/eid0902.020272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hull R N. B virus vaccine. Lab Anim Sci. 1971;21:1068–1071. [PubMed] [Google Scholar]
  14. Jing X, Cerveny M, Yang K, He B. Replication of herpes simplex virus 1 depends on the gamma 134.5 functions that facilitate virus response to interferon and egress in the different stages of productive infection. J Virol. 2004;78:7653–7666. doi: 10.1128/JVI.78.14.7653-7666.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Karr B M, Read G S. The virion host shutoff function of herpes simplex virus degrades the 5′ end of a target mRNA before the 3′ end. Virology. 1999;264:195–204. doi: 10.1006/viro.1999.9986. [DOI] [PubMed] [Google Scholar]
  16. Korom M, Wylie K M, Morrison L A. Selective ablation of virion host shutoff protein RNase activity attenuates herpes simplex virus 2 in mice. J Virol. 2008;82:3642–3653. doi: 10.1128/JVI.02409-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lundberg P, Ramakrishna C, Brown J, Tyszka J M, Hamamura M, Hinton D R, Kovats S, Nalcioglu O, Weinberg K, Openshaw H, Cantin E M. The immune response to herpes simplex virus type 1 infection in susceptible mice is a major cause of central nervous system pathology resulting in fatal encephalitis. J Virol. 2008;82:7078–7088. doi: 10.1128/JVI.00619-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. MacLean A R, ul-Fareed M, Robertson L, Harland J, Brown S M. Herpes simplex virus type 1 deletion variants 1714 and 1716 pinpoint neurovirulence-related sequences in Glasgow strain 17+ between immediate early gene 1 and the ‘a’ sequence. J Gen Virol. 1991;72(Pt3):631–639. doi: 10.1099/0022-1317-72-3-631. [DOI] [PubMed] [Google Scholar]
  19. Mossman K L, Ashkar A A. Herpesviruses and the innate immune response. Viral Immunol. 2005;18:267–281. doi: 10.1089/vim.2005.18.267. [DOI] [PubMed] [Google Scholar]
  20. Ohsawa K, Black D, Ohsawa M, Eberle R. Genome sequence of a pathogenic isolate of monkey B virus (species Macacine herpesvirus 1) Arch Virol. 2014;159(10):2819–2821. doi: 10.1007/s00705-014-2130-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Page H G, Read G S. The virion host shutoff endonuclease (UL41) of herpes simplex virus interacts with the cellular capbinding complex eIF4F. J Virol. 2010;84:6886–6890. doi: 10.1128/JVI.00166-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Pasieka T J, Lu B, Crosby S D, Wylie K M, Morrison L A, Alexander D E, Menachery V D, Leib D A. Herpes simplex virus virion host shutoff attenuates establishment of the antiviral state. J Virol. 2008;82:5527–5535. doi: 10.1128/JVI.02047-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Paul S, Ricour C, Sommereyns C, Sorgeloos F, Michiels T. Type I interferon response in the central nervous system. Biochimie. 2007;89:770–778. doi: 10.1016/j.biochi.2007.02.009. [DOI] [PubMed] [Google Scholar]
  24. Perelygina L, Zhu L, Zurkuhlen H, Mills R, Borodovsky M, Hilliard J K. Complete sequence and comparative analysis of the genome of herpes B virus (Cercopithecine herpesvirus 1) from a rhesus monkey. J Virol. 2003;77:6167–6177. doi: 10.1128/JVI.77.11.6167-6177.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ritchey J W, Ealey K A, Payton M, Eberle R. Comparative pathology of infections with baboon and African green monkey alpha-herpesviruses in mice. J Compar Pathol. 2002;127:150–161. doi: 10.1053/jcpa.2002.0575. [DOI] [PubMed] [Google Scholar]
  26. Rogers K M, Black D H, Eberle R. Primary mouse dermal fibroblast cell cultures as an in vitro model system for the differential pathogenicity of cross-species herpesvirus papio 2 infections. Arch Virol. 2007;152:543–552. doi: 10.1007/s00705-006-0865-1. [DOI] [PubMed] [Google Scholar]
  27. Rogers K M, Deatheridge M, Breshears M A, Chapman S, Black D, Ritchey J W, Payton M, Eberle R. Type I IFN response to Papiine herpesvirus 2 (Herpesvirus papio 2; HVP2) determines neuropathogenicity in mice. Virology. 2009;386:280–289. doi: 10.1016/j.virol.2009.01.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rogers K M, Ritchey J W, Payton M, Black D H, Eberle R. Neuropathogenesis of Herpesvirus papio 2 in Mice Parallels Cercopithecine herpesvirus 1 (B Virus) Infections in Humans. J Gen Virol. 2006;87:267–276. doi: 10.1099/vir.0.81476-0. [DOI] [PubMed] [Google Scholar]
  29. Saffran H A, Read G S, Smiley J R. Evidence for translational regulation by the herpes simplex virus virion host shutoff protein. J Virol. 2010;84:6041–6049. doi: 10.1128/JVI.01819-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Shu M, Taddeo B, Zhang W, Roizman B. Selective degradation of mRNAs by the HSV host shutoff RNase is regulated by the UL47 tegument protein. Proc Natl Acad Sci U S A. 2013;110:E1669–E1675. doi: 10.1073/pnas.1305475110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Simon M A, Daniel M D, Lee-Parritz D, King N W, Ringler D J. Disseminated B virus infection in a cynomolgus monkey. Lab Anim Sci. 1993;43:545–550. [PubMed] [Google Scholar]
  32. Smibert C A, Popova B, Xiao P, Capone J P, Smiley J R. Herpes simplex virus VP16 forms a complex with the virion host shutoff protein vhs. J Virol. 1994;68:2339–2346. doi: 10.1128/jvi.68.4.2339-2346.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Smiley J R, Elgadi M M, Saffran H A. Herpes simplex virus vhs protein. Meth Enzymol. 2001;342:440–451. doi: 10.1016/S0076-6879(01)42565-1. [DOI] [PubMed] [Google Scholar]
  34. Smith T J, Morrison L A, Leib D A. Pathogenesis of herpes simplex virus type 2 virion host shutoff (vhs) mutants. J Virol. 2002;76:2054–2061. doi: 10.1128/jvi.76.5.2054-2061.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Strelow L I, Leib D A. Role of the viron host shutoff (vhs) of herpes simplex virus type 1 in latency and pathogenesis. J Virol. 1995;69:6779–6786. doi: 10.1128/jvi.69.11.6779-6786.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Suzutani T, Nagamine M, Shibaki T, Ogasawara M, Yoshida I, Daikoku T, Nishiyama Y, Azuma M. The role of the UL41 gene of herpes simplex virus type 1 in evasion of non-specific host defence mechanisms during primary infection. J Gen Virol. 2000;81:1763–1771. doi: 10.1099/0022-1317-81-7-1763. [DOI] [PubMed] [Google Scholar]
  37. Taddeo B, Sciortino M T, Zhang W, Roizman B. Interaction of herpes simplex virus RNase with VP16 and VP22 is required for the accumulation of the protein but not for accumulation of mRNA. Proc Natl Acad Sci U S A. 2007;104:12163–12168. doi: 10.1073/pnas.0705245104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Taddeo B, Zhang W, Roizman B. The U(L)41 protein of herpes simplex virus 1 degrades RNA by endonucleolytic cleavage in absence of other cellular or viral proteins. Proc Natl Acad Sci U S A. 2006;103:2827–2832. doi: 10.1073/pnas.0510712103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Taddeo B, Zhang W, Roizman B. The herpes simplex virus host shutoff RNase degrades cellular and viral mRNAs made before infection but not viral mRNA made after infection. J Virol. 2013;87:4516–4522. doi: 10.1128/JVI.00005-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Takeuchi O, Akira S. Recognition of viruses by innate immunity. Immunol Rev. 2007;220:214–224. doi: 10.1111/j.1600-065X.2007.00562.x. [DOI] [PubMed] [Google Scholar]
  41. Zelus B D, Stewart R S, Ross J. The virion host shutoff protein of herpes simplex virus type 1: messenger ribonucleolytic activity in vitro. J Virol. 1996;70:2411–2419. doi: 10.1128/jvi.70.4.2411-2419.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Virologica Sinica are provided here courtesy of Wuhan Institute of Virology, Chinese Academy of Sciences

RESOURCES