Premature expression of the latency-related RNA encoded by bovine herpesvirus type 1 correlates with higher levels of beta interferon RNA expression in productively infected cells
Bovine herpesvirus type 1 (BHV-1) is an important pathogen that can initiate bovine respiratory disease complex. Like other members of the subfamily Alphaherpesvirinae, BHV-1 establishes latency in sensory neurons. The latency-related (LR) gene expresses a family of alternatively spliced transcripts in infected sensory neurons that have the potential to encode several LR proteins. An LR mutant virus that contains three stop codons near the 5′ terminus of the first open reading frame in the LR gene does not express two LR proteins or reactivate from latency. In addition, the LR mutant virus induces higher levels of apoptosis in trigeminal ganglionic neurons and grows less efficiently in certain tissues of infected calves. In spite of the reduced pathogenesis, the LR mutant virus, wild-type BHV-1 and the LR rescued virus exhibit identical growth properties in cultured bovine cells. In this study, we demonstrated that during early phases of productive infection the LR mutant virus expressed higher levels of LR-RNA relative to the LR rescued virus or wt BHV-1. Bovine kidney cells infected with the LR mutant virus also induced higher levels of beta interferon RNA and interferon response genes. These results suggest that inappropriate expression of LR-RNA, in the absence of LR protein expression, may influence the latency-reactivation cycle and pathogenic potential of BHV-1.
AbrilC.,
EngelsM.,
LimmanA.,
HilbeM.,
AlbiniS.,
FranchiniM.,
SuterM.,
AckermanM.2004; Both viral and host factors contribute to neurovirulence of bovine herpesvirus 1 and 5 in interferon receptor-deficient mice. J Virol 78:3644–3653[CrossRef]
BratanichA. C.,
HansonN. D.,
JonesC.1992; The latency-related gene of bovine herpesvirus 1 inhibits the activity of immediate-early transcription unit 1. Virology 191:988–991[CrossRef]
DevireddyL. R.,
JonesC.1998; Alternative splicing of the latency-related transcript of bovine herpesvirus 1 yields RNAs containing unique open reading frames. J Virol 72:7294–7301
DevireddyL. R.,
JonesC.1999; Activation of caspases and p53 by bovine herpesvirus 1 infection results in programmed cell death and efficient virus release. J Virol 73:3778–3788
GeiserV.,
JonesC.2005; The latency related gene encoded by bovine herpesvirus 1 encodes a small regulatory RNA that inhibits cell growth. J Neurovirol 11:563–570[CrossRef]
GeiserV.,
InmanM.,
ZhangY.,
JonesC.2002; 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 83:2965–2971
HendersonG.,
PerngG.-C.,
NesburnA.,
WechslerS.,
JonesC.2004; The latency related gene of bovine herpesvirus 1 can suppress caspase 3 and caspase 9 during productive infection. J Neurovirol 10:64–70[CrossRef]
HendersonG.,
ZhangY.,
JonesC.2005; The bovine herpesvirus 1 gene encoding infected cell protein 0 (bICP0) can inhibit interferon-dependent transcription in the absence of other viral genes. J Gen Virol 86:2697–2702[CrossRef]
HohleC.,
KargerA.,
KonigP.,
GlesowK.,
KeilG. M.2005; High-level expression of biologically active bovine alpha interferon by Bovine herpesvirus 1 interferes only marginally with recombinant virus replication in vitro. J Gen Virol 86:2685–2695[CrossRef]
InmanM.,
LovatoL.,
DosterA.,
JonesC.2001; A mutation in the latency-related gene of bovine herpesvirus 1 leads to impaired ocular shedding in acutely infected calves. J Virol 75:8507–8515[CrossRef]
InmanM.,
LovatoL.,
DosterA.,
JonesC.2002; A mutation in the latency related gene of bovine herpesvirus 1 interferes with the latency-reactivation cycle of latency in calves. J Virol 76:6771–6779[CrossRef]
InmanM.,
ZhouJ.,
WebbH.,
JonesC.2004; 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 78:5438–5447[CrossRef]
JiangY.,
HossainA.,
WinklerM. T.,
HoltT.,
DosterA.,
JonesC.1998; 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 72:8133–8142
JiangY.,
InmanM.,
ZhangY.,
PosadasN. A.,
JonesC.2004; 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 78:3184–3189[CrossRef]
KutishG.,
MainprizeT.,
RockD.1990; Characterization of the latency-related transcriptionally active region of the bovine herpesvirus 1 genome. J Virol 64:5730–5737
LinR.,
NoyceR. S.,
CollinsS. E.,
EverettR. D.,
MossmanK. L.2004; The herpes simplex virus ICP0 RING finger domain inhibits IRF3- and IRF7-mediated activation of interferon-stimulated genes. J Virol 78:1675–1684[CrossRef]
LovatoL.,
InmanM.,
HendersonG.,
DosterA.,
JonesC.2003; 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 77:4848–4857[CrossRef]
MegyeriK.,
AuW.-C.,
RosztoczyI.,
BabuN.,
RajK.,
MillerR. L.,
TomaiM. A.,
PithaP. M.1995; Stimulation of interferon and cytokine gene expression by imiquimod and stimulation by Sendai virus utilize similar signal transduction pathways. Mol Cell Biol 15:2207–2218
MeyerF.,
PerezS.,
JiangY.,
ZhouY.,
HendersonG.,
JonesC.2007; Identification of a novel protein encoded by the latency related (LR) gene of bovine herpesvirus 1 (BHV-1. J Neurovirol 13:569–578[CrossRef]
PerezS.,
LovatoL.,
ZhouJ.,
DosterA.,
JonesC.2006; Comparison of inflammatory infiltrates in trigeminal ganglia of cattle infected with wild type BHV-1 versus a virus strain containing a mutation in the LR (latency-related) gene. J Neurovirol 12:392–397[CrossRef]
PetersG. A.,
KhooD.,
MohrI.,
SenG. C.2002; Inhibition of PACT-mediated activation of PKR by the herpes simplex simplex virus type 1 Us11 protein. J Virol 75:11054–11064
SchangL. M.,
JonesC.1997; Analysis of bovine herpesvirus 1 transcripts during a primary infection of trigeminal ganglia of cattle. J Virol 71:6786–6795
SchangL. M.,
HossainA.,
JonesC.1996; The latency-related gene of bovine herpesvirus 1 encodes a product which inhibits cell cycle progression. J Virol 70:3807–3814
ValarcherJ.-F.,
FurzeJ.,
WyldS.,
CookR.,
ConzelmanK.-K.,
TaylorG.2003; Role of alpha/beta interferons in the attenuation and immunogenecity of recombinant bovine respiratory syncytial viruses lacking NS proteins. J Virol 77:8426–8439[CrossRef]
WilsonV.,
JeffreysA. J.,
BarrieP. A.1983; A comparison of vertebrate interferon gene families detected by hybridization with human interferon DNA. J Mol Biol 166:457–475[CrossRef]
WinklerM. T.,
DosterA.,
JonesC.1999; Bovine herpesvirus 1 can infect CD4+ T lymphocytes and induce programmed cell death during acute infection of cattle. J Virol 73:8657–8668
WinklerM. T. C.,
DosterA.,
JonesC.2000; Persistence and reactivation of bovine herpesvirus 1 in the tonsil of latently infected calves. J Virol 74:5337–5346[CrossRef]
WinklerM. T.,
DosterA.,
SurJ. H.,
JonesC.2002; Analysis of bovine trigeminal ganglia following infection with bovine herpesvirus 1. Vet Microbiol 86:139–155[CrossRef]
ZhangY.,
JiangY.,
ZhouJ.,
JonesC.2006; The bovine herpes virus 1 (BHV-1) immediate early protein (bICP0) interacts with the histone acetyltransferase p300, and these interactions correlate with stimulation of gC promoter activity. J Gen Virol 87:1843–1851[CrossRef]
Premature expression of the latency-related RNA encoded by bovine herpesvirus type 1 correlates with higher levels of beta interferon RNA expression in productively infected cells