Abstract
Bovine herpesvirus type 1 and type 5 (BoHV-1 and BoHV-5) are two alphaherpesviruses that affect cattle with two different syndromes. While BoHV-1 mainly produces respiratory symptoms, BoHV-5 is highly neuropathogenic and responsible for meningoencephalitis in young cattle. The latency-related (LR) gene, which is not conserved between these two herpesviruses, is the only viral gene abundantly expressed in latently infected neurons. The antiapoptotic action of this gene has been demonstrated during acute infection and reactivation from latency and seems to be mainly mediated by a LR protein (ORF-2) which is truncated in amino acid 51 in the case of BoHV-5. In this work, we show that the BoHV-5 LR gene is less efficient at cell survival and apoptosis inhibition in transient as well as in established neuronal cell lines compared to its BoHV-1 homolog. We hypothesize that the BoHV-5 LR gene may have novel functions that are lacking in the BoHV-1 LR gene and that these differences may contribute to its enhanced neuropathogenesis.
References
Beltrão NFE, Weiblen R, Silva AM, Roehe PM, Irigoyen LF (2001) Infacçao e enfermidade neurológica pelo herpesvirus bovino tipo 5 (BHV-5): coelhos como modelo experimental. Pesqui Vet Bras 20:144–150
Ciacci-Zanella J, Stone M, Henderson G, Jones C (1999) The latency-related gene of bovine herpesvirus 1 inhibits programmed cell death. J Virol 73:9734–9740
Delhon G, Moraes MP, Lu Z, Afonso CL, Flores EF, Weiblen R, Kutish GF, Rock DL (2003) Genome of bovine herpesvirus 5. J Virol 77:10339–10347
Devireddy LR, Jones C (1998) Alternative splicing of the latency-related transcript of bovine herpesvirus 1 yields RNAs containing unique open reading frames. J Virol 72:7294–7301
Gordeev SA, Bykova TV, Zubova SG, Bystrova OA, Martynova MG, Pospelov VA, Pospelova TV (2015) mTOR kinase inhibitor pp242 causes mitophagy terminated by apoptotic cell death in E1A-Ras transformed cells. Oncotarget 6:44905–44926
Inman M, Perng GC, Henderson G, Ghiasi H, Nesburn AB, Wechsler SL, Jones C (2001) Region of herpes simplex virus type 1 latency-associated transcript sufficient for wild-type spontaneous reactivation promotes cell survival in tissue culture. J Virol 75:3636–3646
Jones C (2003) Herpes simplex virus type 1 and bovine herpesvirus 1 latency. Clin Microbiol Rev 16:79–95
Jones C (2013) Bovine herpes virus 1 (BHV-1) and herpes simplex virus type 1 (HSV-1) promote survival of latently infected sensory neurons, in part by inhibiting apoptosis. J Cell Death 6:1–16
Jones C, da Silva LF, Sinani D (2011) Regulation of the latency-reactivation cycle by products encoded by the bovine herpesvirus 1 (BHV-1) latency-related gene. J Neuro-Oncol 17:535–545
Lovato L, Inman M, Henderson G, Doster A, Jones C (2003) Infection of cattle with a bovine herpesvirus 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 77:4848–4857
Meyer F, Perez S, Geiser V, Sintek M, Inman M, Jones C (2007a) A protein encoded by the bovine herpesvirus 1 latency-related gene interacts with specific cellular regulatory proteins, including CCAAT enhancer binding protein alpha. J Virol 81:59–67
Meyer F, Perez S, Jiang Y, Zhou Y, Henderson G, Jones C (2007b) Identification of a novel protein encoded by the latency-related gene of bovine herpesvirus 1. J Neuro-Oncol 13:569–578
Perez SE, Bretschneider G, Leunda MR, Osorio EA, Flores EF, Odeon AC (2002) Primary infection, latency, and reactivation of bovine herpesvirus type 5 in the bovine nervous system. Vet Pathol 39:437–444
Perng GC, Slanina SM, Yukht A, Ghiasi H, Nesburn AB, Wechsler SL (2000) The latency-associated transcript gene enhances establishment of herpes simplex virus type 1 latency in rabbits. J Virol 74:1885–1891
Rahbar Saadat Y, Saeidi N, Zununi Vahed S, Barzegari A, Barar J (2015) An update to DNA ladder assay for apoptosis detection. Bioimpacts 5:25–28
Shen W, Jones C (2008) Open reading frame 2, encoded by the latency-related gene of bovine herpesvirus 1, has antiapoptotic activity in transiently transfected neuroblastoma cells. J Virol 82:10940–10945
Silvestro C, Bratanich A (2016) The latency related gene of bovine herpesvirus types 1 and 5 and its modulation of cellular processes. Arch Virol 161:3299–3308
Sinani D, Jones C (2011) Localization of sequences in a protein (ORF2) encoded by the latency-related gene of bovine herpesvirus 1 that inhibits apoptosis and interferes with Notch1-mediated trans-activation of the bICP0 promoter. J Virol 85:12124–12133
Sinani D, Liu Y, Jones C (2014) Analysis of a bovine herpesvirus 1 protein encoded by an alternatively spliced latency related (LR) RNA that is abundantly expressed in latently infected neurons. Virology 464-465:244–252
Tone S, Sugimoto K, Tanda K, Suda T, Uehira K, Kanouchi H, Samejima K, Minatogawa Y, Earnshaw WC (2007) Three distinct stages of apoptotic nuclear condensation revealed by time-lapse imaging, biochemical and electron microscopy analysis of cell-free apoptosis. Exp Cell Res 313:3635–3644
Vogel FS, Caron L, Flores EF, Weiblen R, Winkelmann ER, Mayer SV, Bastos RG (2003) Distribution of bovine herpesvirus type 5 DNA in the central nervous systems of latently, experimentally infected calves. J Clin Microbiol 41:4512–4520
Acknowledgments
We would like to thank Fiorella Kotsias for reviewing the manuscript and providing valuable suggestions.
Funding
This study was supported by Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT, Argentina) PICT 2010-0925 to ACB. CS was granted a scholarship type I from ANPCyT and a type II scholarship from Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET).
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Silvestro, C., Jones, C. & Bratanich, A. Functional analysis of the latency-related gene of bovine herpesvirus types 1 and 5. J. Neurovirol. 25, 597–604 (2019). https://doi.org/10.1007/s13365-019-00745-y
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DOI: https://doi.org/10.1007/s13365-019-00745-y