Department of Veterinary and Biomedical Sciences, Nebraska Center for Virology and School of Biological Sciences, University of Nebraska, Lincoln, NE 68583, USA
Correspondence
C. Jones
cjones{at}unlnotes.unl.edu
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Calves infected acutely with BHV-1 contain high levels of apoptotic CD4+ T cells compared with mock-infected calves (Winkler et al., 1999, 2000
). Viral antigens and apoptotic cells localize to germinal centres of pharyngeal tonsil in acutely or latently infected calves. BHV-1 induces apoptosis when cultured T cells, B lymphocytes or monocytes are infected (Hanon et al., 1996
, 1998
). Glycoprotein D (Hanon et al., 1999
), c-myc induction (Hanon et al., 1997
), p53 expression and caspase activation (Devireddy & Jones, 1999
) play a role in BHV-1-induced apoptosis. As BHV-1 infects lymphoid cells and induces apoptosis, peripheral blood mononuclear cells prepared from calves infected acutely with BHV-1 produce less interleukin 2, have a reduced mitogenic response and exhibit lower natural cytotoxic activities (Carter et al., 1989
). BHV-1 also interferes with major histocompatibility complex class I antigen presentation and cytotoxic lymphocyte-mediated killing of virus-infected cells (Hariharan et al., 1993
; Nataraj et al., 1997
; reviewed by Favoreel et al., 2000
). Collectively, these studies indicate that BHV-1 suppresses the immune system of acutely infected calves by several different mechanisms.
Viral gene expression is regulated temporally in three distinct phases: immediate-early (IE), early (E) and late (L) (Jones, 2003). The bICP0 protein is encoded by IE transcription unit 1 (IEtu1) (Wirth et al., 1992
), is expressed constitutively during productive infection because it has an IE and E promoter, and activates its own promoters (Fig. 1a
) (Fraefel et al., 1994
). When BHV-1 DNA is transfected into permissive cells, plaque formation is inefficient. Co-transfection of BHV-1 DNA with bICP0 significantly increases the number of plaques and decreases the time taken for plaques to appear (Geiser & Jones, 2003
; Inman et al., 2001b
), indicating that bICP0 stimulates productive infection. bICP0 associates with histone deacetylase 1 (HDAC1) and, in quiescent cells, bICP0 relieves HDAC1-induced transcriptional repression (Zhang & Jones, 2001
), suggesting that this activity promotes viral transcription.
|
A bICP0 mutant was constructed previously by inserting the -galactosidase gene into bICP0-coding sequences (Koppel et al., 1996
). This mutant was not stable because viral sequences were not deleted and, thus, wild-type (wt) virus could be regenerated when the virus was passaged in cultured cells. HSV-1 ICP0 mutants have impaired growth in culture, but the defect in virus production is reduced when infection is conducted at a high m.o.i. (Sacks & Schaffer, 1987
; Stow & Stow, 1986
). In a human tumour-cell line, U2-OS, ICP0 mutants have wt growth properties, suggesting that cellular factors can substitute for ICP0 functions (Yao & Schaffer, 1995
).
In this study, we generated a bICP0 null mutant that did not express detectable levels of the bICP0 protein. Although bICP0 was not required for growth of BHV-1 in cultured bovine cells, expression was necessary for efficient growth and plaque formation. These studies also suggested that the bICP0 null mutant virus established a persistent-like infection in bovine kidney cells.
![]() |
METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The pbICP0x construct was constructed by cloning the XbaIAscI fragment (genome nt 100236103953) of plasmid phd/k into pUC19. Plasmid phd/k was digested with HindIII plus XbaI, blunt-ended, ligated, digested with AscI and then religated. The resulting plasmid was digested with BstXI, blunt-ended and HindIII linkers were added to form phd/K+. Plasmids phd/K+ and mbICP0 were digested with HindIII and SalI. The HindIIISalI fragment obtained from plasmid mbICP0 was gel-purified and ligated into phd/K+ to generate pbICP0x (Fig. 1b). All plasmids were transformed and maintained in the DH5
strain of Escherichia coli (Life Technologies).
Cells.
MadinDarby bovine kidney (MDBK) cells were plated at a density of 5x105 cells per 100 mm2 plastic dish in Earle's modified Eagle's medium supplemented with 5 % fetal bovine serum (FBS), penicillin (10 U ml1) and streptomycin (100 µl ml1). MDBK cells were split in a 1 : 8 ratio every 3 days. The bovine cell line 9.1.3 was supplemented with medium containing 10 % FBS and split in a 1 : 6 ratio every 3 days, as described previously (Inman et al., 2001b).
Virus.
The Cooper strain of BHV-1 (wt virus) was obtained from the National Veterinary Services Laboratory, Animal and Plant Health Inspection Services, Ames, IA, USA. Viral stocks were prepared by infecting MDBK cells at an m.o.i. of 0·01 from plaque-purified virus and subsequently titrating on MDBK cells.
Extraction of viral genomic DNA.
MDBK cells were infected with wt BHV-1 Cooper strain, the rescued virus or the bICP0 null mutant virus (m.o.i., 0·01) and viral genomic DNA was extracted as described previously (Inman et al., 2001a, b
). At 3672 h after infection [cytopathic effect (CPE) of approximately 80 %], the supernatant was collected and clarified by centrifugation (7000 r.p.m., 4 °C, 20 min in a Beckman J2-21 using a JA-20 rotor). Virus in the supernatant was pelleted through a 30 % sucrose/TE cushion (25 ml virus per 5 ml sucrose solution) by centrifugation (25 000 r.p.m., 4 °C, 2 h in a Beckman L7-65 ultracentrifuge using an SW28 rotor). The pellet was suspended in 623 µl RSB buffer [10 mM Tris/HCl (pH 7·4), 10 mM KCl, 1·5 mM MgCl] and then treated with 6·3 µl DNase I (105 U ml1) at 37 °C for 2 h. The reaction was stopped by adding 90 µl 20 mM EDTA and incubating at 65 °C for 15 min. The suspension was diluted with 24·3 ml calcium- and magnesium-free PBS (CMF-PBS) and the virus was pelleted as described above. The pellet was suspended in 1·8 ml DNase I-free TE. Virions were disrupted by adding 100 µl 20 % SDS, 15 µg RNase and incubating the solution at 37 °C for 30 min. Proteinase K (10 mg) was then added and the solution was incubated at 65 °C for 30 min. Three phenol/chloroform/isoamyl alcohol (50 : 48 : 2) extractions were performed, followed by one extraction with chloroform/isoamyl alcohol (48 : 2). The aqueous phase was extracted with ether three times. Following ethanol precipitation, viral DNA was electrophoresed on an agarose gel to examine its quality and quantity. Known concentrations of DNA standards were used to estimate the amounts of viral DNA.
Transfections and identification of the bICP0 mutant.
Bovine 9.1.3 cells were co-transfected with 2 µg viral genomic DNA, 6 µg pbICP0x (or phd/k) plasmid and increasing amounts of an HSV-1 ICP0 expression plasmid (0, 0·25, 0·5, 1 or 2 µg) by using Superfect (Qiagen) as described previously (Inman et al., 2001a).
The sequence of the region of the bICP0 mutant virus, the rescued virus and pbICP0x was determined by PCR amplification using primers bICP0a and bICP0b as described below and shown in Fig. 1(b). The PCR products were cloned into the TOPO vector and the insert was sequenced.
PCR.
PCR was performed with DNA extracted from infected MDBK cells at 48 h after infection. PCR was conducted with 5 µl 10x commercial PCR buffer, 2 µl 25 mM MgCl2, 10 µl GC-Melt (BD), 1 µl 40 mM dNTPs, 1 µM each primer and 1 U Taq polymerase for each 50 µl reaction. To detect the bICP0 null mutant, PCR was performed on extracted DNA by using the bICP0a (nt 102828102845, 5'-GCCTTTCGCCGCCCGCCC-3') and bICP0b (nt 102469102452, 5'-CAACGCGCCGTCCGCCCC-3') primers. The bICP0 region of the mutant virus was also amplified by using primers bICP0a and bICP0b-EcoRI (5'-CGGAATTCAACGCGCCGTCCGCCCC-3') and then cloned into pUC19.
The bICP22 primers were 5'-GCGCTGGTCCTCCGGCTCC-3' (upstream primer) and 5'-CTCGCTGGCGGCGCTTGG-3' (downstream primer) (Schang & Jones, 1997). The latency-related (LR) gene and bICP0 primers were 5'-TTCTCTGGGCTCGGGGCTGC-3' and 5'-AGAGGTCGACAAACACCCGCGGT-3' (L3B primers) (Hossain et al., 1995
). The glycoprotein C (gC) primers were 5'-GAGCAAAGCCCCGCCGAAGGA-3' and 5'-TACGAACAGCAGCACGGGCGG-3' (Schang & Jones, 1997
).
After a hot start for 3 min, each PCR cycle consisted of 95 °C for 30 s, incubation at the annealing temperature for the indicated time and 72 °C for 1 min. The annealing temperatures and times were as follows: bICP0, 66·6 °C, 45 s; bICP22, 65 °C, 45 s; L3B, 65 °C, 1 min; gC, 63 °C, 45 s. PCR was carried out for 35 cycles (bICP0, bICP22, gC) or 40 cycles (L3B). To ensure complete elongation of the amplified products, the reaction mixture was incubated at 72 °C for an additional 10 min. PCR products were electrophoresed on a 2 % agarose gel and the DNA was visualized by ethidium bromide staining.
Measurement of virus titres in bovine cells.
MDBK cells were infected at an m.o.i. of 0·01 for the designated viruses (1 h at 37 °C). Cultures were then rinsed twice with CMF-PBS and complete medium was added. Supernatant from infected cultures or cell lysate was subjected to three freezethaw cycles. After cell debris had been pelleted, the supernatant was titrated on MDBK cells. The final dilution eliciting a CPE was determined for each sample.
At 48 h post-infection (p.i.), total cell lysate was collected and subjected to three freezethaw cycles. Virions were pelleted by using a sucrose cushion and treated with DNase I to remove cellular and non-encapsidated DNA. Total viral genomic DNA was purified as described above for extraction of viral genomic DNA and the DNA was analysed by gel electrophoresis. The equivalent of a 100 mm plate was loaded for each virus, along with 10-fold dilutions of the bICP0 rescued virus to facilitate quantification. Total virion genomic DNA was quantified by using a ChemiDoc XRS imaging system and analysed with the Quantity One program (Bio-Rad).
Protein analysis.
To determine protein levels of bICP0 and -actin, whole-cell lysate was prepared by using a high/low-salt lysis procedure as described previously (Zhang & Jones, 2001
). Proteins in the gel were transferred to Immobilon P membranes (Millipore) and Western blotting was performed as described previously (Hossain et al., 1995
; Inman et al., 2001b
).
To estimate viral protein levels, virions were collected at 48 h p.i. and purified virions suspended in 60 µl per 100 mm2 plate of 2x lysis buffer [7·84 mM Tris/HCl (pH 8·0), 39·2 mM NaCl, 0·784 mM EDTA, 2 mg iodoacetamide ml1, 0·05 mM sodium fluoride, 10 mM sodium pyrophosphate, 1 mM sodium o-vanadate, 5 µg leupeptin ml1, 5 µg pepstatin ml1, 5 µg antipain ml1, 10 mM PMSF]. Boiling 10 % SDS (60 µl) was added to the cell pellet from a 100 mm dish, the sample was vortexed and the solution was boiled for 5 min. Samples were centrifuged for 5 min at 4 °C (15 000 r.p.m.) in a Beckman Avanti 30 centrifuge. The supernatant was transferred to a new tube along with 120 µl per 100 mm2 plate of 2x sample buffer [62·5 mM Tris/HCl (pH 6·8), 2 % SDS, 50 mM dithiothreitol, 0·1 % bromophenol blue, 10 % glycerol]. The cell lysate was boiled for 5 min and the proteins separated by 10 % SDS-PAGE. BHV-1-specific antibodies were detected by Western blotting with a primary anti-BHV-1 serum (VMRD) diluted 1 : 500. Detection of proteins was conducted by using a secondary donkey anti-goat antibody (Santa Cruz Biotechnology) diluted 1 : 2000.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Plasmid pbICP0x contained the entire coding sequence of bICP0 with at least 1 kb of flanking sequences on both sides of the zinc RING finger mutations to facilitate homologous recombination with BHV-1 (Fig. 1b). The zinc RING finger contained mutations at aa 13 (C
G) and aa 51 (C
A) (Inman et al., 2001b
). The mutation at aa 51 had a unique MscI restriction site to allow identification of the mutation (Fig. 1c
). A unique HindIII restriction site was also present in pbICP0x to facilitate screening. A plasmid encoding HSV-1 ICP0 was co-transfected with BHV-1 DNA and pbICP0x into bovine cells to stimulate plaque formation. ICP0 or bICP0 stimulates the number of plaques and reduces the time for plaque formation when cells are transfected with BHV-1 DNA (Geiser, 2001
; Geiser & Jones, 2003
; Inman et al., 2001b
). Three days after transfection, cultures were subjected to three freezethaw cycles and the virus in the supernatant was allowed to form plaques on MDBK cells. A small area of infected cells resembling a plaque was identified. After three rounds of plaque purification, this virus maintained the small-plaque phenotype (Fig. 2a
). Cells comprising the small plaque were distinct from mock-infected cells (Fig. 2c
) and did not yield the typical plaques observed following infection of MDBK cells with wt BHV-1 (Fig. 2b
). The putative bICP0 mutant was rescued by using a plasmid containing the wt bICP0 gene and designated bICP0-rescued virus. The bICP0-rescued virus yielded plaques that were indistinguishable from those produced by wt BHV-1 (Fig. 2d
).
|
|
|
|
|
Total virion proteins were also detected by Western blot analysis using antiserum directed against BHV-1. Lower levels of viral proteins were detected in MDBK cells infected with the bICP0 null mutant relative to cells infected with wt or the bICP0-rescued virus (Fig. 6d).
Survival of MDBK cells infected with the bICP0 null mutant virus
As the bICP0 null mutant virus was not as cytotoxic as wt BHV-1 or the bICP0-rescued virus, we tested whether MDBK cultures infected with the bICP0 null mutant were capable of growing. When MDBK cells were infected with the bICP0 null mutant, we were able to subculture the infected cells at least 35 times. Cultures infected with the bICP0 null mutant contained numerous cells with rounded nuclei and/or elongated fusiform morphology (Fig. 7a) relative to mock-infected cells (Fig. 7b
). Viral DNA was detected by PCR using primers that detected several different viral genes after 12 passages (Fig. 7c
) and following 35 passages (data not shown). After 14 passages, low levels of virion DNA and infectious virus were detected in the supernatant of MDBK cells infected with the bICP0 null mutant (data not shown). Collectively, these studies suggested that the bICP0 null mutant induced a persistent infection in MDBK cells because the infected cells survived, the cultures contained viral DNA and low levels of infectious virus were released from cultures.
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In general, the phenotype of the bICP0 null mutant was similar to that of HSV-1 ICP0 null mutants, as ICP0 is not required for growth in cultured cells (Sacks & Schaffer, 1997; Stow & Stow, 1986
). Although bICP0 protein expression was not absolutely required for productive infection in bovine cells, there was a marked reduction in infectious virus and the mutant did not form clear-cut plaques. One reason why the bICP0 null mutant virus did not grow efficiently is that bICP0 activates viral transcription (Fraefel et al., 1994
; Inman et al., 2001b
; Wirth et al., 1992
; Zhang & Jones, 2001
). We also predicted that other bICP0 functions enhance productive infection and virus yield. For example, we have recently discovered that bICP0 inhibits beta interferon (IFN-
) promoter activity in transient-transfection assays (Y. Zhang & C. Jones, unpublished data). HSV-1 genes encoding ICP0, 34.5 and US11 inhibit the IFN response and do not grow efficiently (Katze et al., 2002
; Mossman & Smiley, 2002
; Mossman et al., 2000
, 2001
). BHV-1 apparently does not encode a 34.5 homologue, suggesting that bICP0 is the major viral protein that inhibits the IFN response. Mice lacking type I and type II IFN receptors in combination with RAG-2 gene deletions die within a few days of infection with BHV-1 (Abril et al., 2004
). BHV-1 infection of wt mice does not lead to clinical symptoms, underscoring the importance of the IFN-signalling pathways and BHV-1 replication. In summary, activation of transcription and inhibition of IFN-dependent transcription are two bICP0 functions that are likely to be necessary for efficient productive infection.
When the HSV-1 ICP0 gene is deleted, the viral genome is maintained persistently, but cytotoxicity is reduced (Samaniego et al., 1998). A similar situation apparently occurred following infection of MDBK cells with the bICP0 null mutant (Fig. 7
). To date, MDBK cells infected with the bICP0 null mutant have been subcultured more than 35 times and the viral genome is still detected. We recently demonstrated that bICP0 indirectly induces caspase 3, which leads to apoptosis (Henderson et al., 2004
). In the absence of bICP0, BHV-1 infection may not induce a strong apoptotic response, which is indicative of infection with wt virus (Devireddy & Jones, 1999
). Our studies suggested that cells infected with the bICP0 null mutant survived for numerous passages and produced low levels of infectious virus. Although we were able to detect infectious virus in the persistently infected cultures, we do not know whether the genome was maintained stably in all infected cells and what percentage of infected cells produced virus. Additional studies will be necessary to understand these complex virushost interactions fully.
We recently generated a panel of bICP0 transposon mutants (Zhang et al., 2005). This study revealed that bICP0 contains several important functional domains: (i) the zinc RING finger; (ii) two separate domains that activate transcription; and (iii) a C-terminal nuclear-localization sequence that is necessary for efficient transactivation. We believe that these mutations can be recombined readily into the bICP0 null mutant, because the fitness of the bICP0 null mutant should be improved. Consequently, it should be possible to generate additional bICP0 mutants with specific mutations in the bICP0 protein-coding sequences. These mutants will be useful to help us understand the function of bICP0 in the context of productive infection and the latency-reactivation cycle in cattle.
![]() |
ACKNOWLEDGEMENTS |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Boutell, C., Sadis, S. & Everett, R. D. (2002). Herpes simplex virus type 1 immediate-early protein ICP0 and its isolated RING finger domain act as ubiquitin E3 ligases in vitro. J Virol 76, 841850.
Carter, J. J., Weinberg, A. D., Pollard, A., Reeves, R., Magnuson, J. A. & Magnuson, N. S. (1989). Inhibition of T-lymphocyte mitogenic responses and effects on cell functions by bovine herpesvirus 1. J Virol 63, 15251530.[Medline]
Devireddy, L. R. & Jones, C. J. (1999). Activation of caspases and p53 by bovine herpesvirus 1 infection results in programmed cell death and efficient virus release. J Virol 73, 37783788.
Everett, R. D. (1987). A detailed mutational analysis of Vmw110, a trans-acting transcriptional activator encoded by herpes simplex virus type 1. EMBO J 6, 20692076.[Abstract]
Everett, R. D. (1988). Analysis of the functional domains of herpes simplex virus type 1 immediate-early polypeptide Vmw110. J Mol Biol 202, 8796.[CrossRef][Medline]
Everett, R. D., Barlow, P., Milner, A., Luisi, B., Orr, A., Hope, G. & Lyon, D. (1993). A novel arrangement of zinc-binding residues and secondary structure in the C3HC4 motif of an alpha herpes virus protein family. J Mol Biol 234, 10381047.[CrossRef][Medline]
Everett, R. D., Meredith, M., Orr, A., Cross, A., Kathoria, M. & Parkinson, J. (1997). A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein. EMBO J 16, 15191530.
Everett, R. D., Earnshaw, W. C., Findlay, J. & Lomonte, P. (1999a). Specific destruction of kinetochore protein CENP-C and disruption of cell division by herpes simplex virus immediate-early protein Vmw110. EMBO J 18, 15261538.
Everett, R. D., Lomonte, P., Sternsdorf, T., van Driel, R. & Orr, A. (1999b). Cell cycle regulation of PML modification and ND10 composition. J Cell Sci 112, 45814588.
Favoreel, H. W., Nauwynck, H. J. & Pensaert, M. B. (2000). Immunological hiding of herpesvirus-infected cells. Arch Virol 145, 12691290.[CrossRef][Medline]
Fraefel, C., Zeng, J., Choffat, Y., Engels, M., Schwyzer, M. & Ackermann, M. (1994). Identification and zinc dependence of the bovine herpesvirus 1 transactivator protein BICP0. J Virol 68, 31543162.[Abstract]
Fuchs, M., Hübert, P., Detterer, J. & Rziha, H.-J. (1999). Detection of bovine herpesvirus type 1 in blood from naturally infected cattle by using a sensitive PCR that discriminates between wild-type virus and virus lacking glycoprotein E. J Clin Microbiol 37, 24982507.
Geiser, V. (2001). Regulation of productive bovine herpesvirus 1 infection by bICP0, latency related gene, and pocket proteins, and E2F family members. MSc thesis, University of Nebraska-Lincoln, NE, USA.
Geiser, V. & Jones, C. (2003). Stimulation of bovine herpesvirus-1 productive infection by the adenovirus E1A gene and a cell cycle regulatory gene, E2F-4. J Gen Virol 84, 929938.
Hanon, E., Vanderplasschen, A., Lyaku, S., Keil, G., Denis, M. & Pastoret, P.-P. (1996). Inactivated bovine herpesvirus 1 induces apoptotic cell death of mitogen-stimulated bovine peripheral blood mononuclear cells. J Virol 70, 41164120.[Abstract]
Hanon, E., Hoornaert, S., Dequiedt, F., Vanderplasschen, A., Lyaku, J., Willems, L. & Pastoret, P.-P. (1997). Bovine herpesvirus 1-induced apoptosis occurs at the G0/G1 phase of the cell cycle. Virology 232, 351358.[CrossRef][Medline]
Hanon, E., Meyer, G., Vanderplasschen, A., Dessy-Doizé, C., Thiry, E. & Pastoret, P.-P. (1998). Attachment but not penetration of bovine herpesvirus 1 is necessary to induce apoptosis in target cells. J Virol 72, 76387641.
Hanon, E., Keil, G., van Drunen Little-van den Hurk, S., Griebel, P., Vanderplasschen, A., Rijsewijk, F. A. M., Babiuk, L. & Pastoret, P.-P. (1999). Bovine herpesvirus 1-induced apoptotic cell death: role of glycoprotein D. Virology 257, 191197.[CrossRef][Medline]
Hariharan, M. J., Nataraj, C. & Srikumaran, S. (1993). Down regulation of murine MHC class I expression by bovine herpesvirus 1. Viral Immunol 6, 273284.[Medline]
Henderson, G., Zhang, Y., Inman, M., Jones, D. & Jones, C. (2004). Infected cell protein 0 encoded by bovine herpesvirus 1 can activate caspase 3 when overexpressed in transfected cells. J Gen Virol 85, 35113516.
Hobbs, W. E., II & DeLuca, N. A. (1999). Perturbation of cell cycle progression and cellular gene expression as a function of herpes simplex virus ICP0. J Virol 73, 82458255.
Hossain, A., Schang, L. M. & Jones, C. (1995). Identification of gene products encoded by the latency-related gene of bovine herpesvirus 1. J Virol 69, 53455352.[Abstract]
Inman, M., Lovato, L., Doster, A. & Jones, C. (2001a). A mutation in the latency-related gene of bovine herpesvirus 1 leads to impaired ocular shedding in acutely infected calves. J Virol 75, 85078515.
Inman, M., Zhang, Y., Geiser, V. & Jones, C. (2001b). The zinc ring finger in the bICP0 protein encoded by bovine herpesvirus-1 mediates toxicity and activates productive infection. J Gen Virol 82, 483492.
Jones, C. (1998). Alphaherpesvirus latency: its role in disease and survival of the virus in nature. Adv Virus Res 51, 81133.[Medline]
Jones, C. (2003). Herpes simplex virus type 1 and bovine herpesvirus 1 latency. Clin Microbiol Rev 16, 7995.
Katze, M. G., He, Y. & Gale, M., Jr (2002). Viruses and interferon: a fight for supremacy. Nat Rev Immunol 2, 675687.[CrossRef][Medline]
Koppel, R., Fraefel, C., Vogt, B., Bello, L. J., Lawrence, W. C. & Schwyzer, M. (1996). Recombinant bovine herpesvirus-1 (BHV-1) lacking transactivator protein BICP0 entails lack of glycoprotein C and severely reduced infectivity. Biol Chem 377, 787795.[Medline]
Lomonte, P. & Everett, R. D. (1999). Herpes simplex virus type 1 immediate-early protein Vmw110 inhibits progression of cells through mitosis and from G1 into S phase of the cell cycle. J Virol 73, 94569467.
Maul, G. G. & Everett, R. D. (1994). The nuclear location of PML, a cellular member of the C3HC4 zinc-binding domain protein family, is rearranged during herpes simplex virus infection by the C3HC4 viral protein ICP0. J Gen Virol 75, 12231233.[Abstract]
Maul, G. G., Guldner, H. H. & Spivack, J. G. (1993). Modification of discrete nuclear domains induced by herpes simplex virus type 1 immediate early gene 1 product (ICP0). J Gen Virol 74, 26792690.[Abstract]
Mossman, K. L. & Smiley, J. R. (2002). Herpes simplex virus ICP0 and ICP34.5 counteract distinct interferon-induced barriers to virus replication. J Virol 76, 19951998.
Mossman, K. L., Saffran, H. A. & Smiley, J. R. (2000). Herpes simplex virus ICP0 mutants are hypersensitive to interferon. J Virol 74, 20522056.
Mossman, K. L., Macgregor, P. F., Rozmus, J. J., Goryachev, A. B., Edwards, A. M. & Smiley, J. R. (2001). Herpes simplex virus triggers and then disarms a host antiviral response. J Virol 75, 750758.
Mweene, A. S., Okazaki, K. & Kida, H. (1996). Detection of viral genome in non-neural tissues of cattle experimentally infected with bovine herpesvirus 1. Jpn J Vet Res 44, 165174.[Medline]
Nataraj, C., Eidmann, S., Hariharan, M. J., Sur, J. H., Perry, G. A. & Srikumaran, S. (1997). Bovine herpesvirus 1 downregulates the expression of bovine MHC class I molecules. Viral Immunol 10, 2134.[Medline]
Parkinson, J. & Everett, R. D. (2000). Alphaherpesvirus proteins related to herpes simplex virus type 1 ICP0 affect cellular structures and proteins. J Virol 74, 1000610017.
Rock, D., Lokensgard, J., Lewis, T. & Kutish, G. (1992). Characterization of dexamethasone-induced reactivation of latent bovine herpesvirus 1. J Virol 66, 24842490.[Abstract]
Sacks, W. R. & Schaffer, P. A. (1987). Deletion mutants in the gene encoding the herpes simplex virus type 1 immediate-early protein ICP0 exhibit impaired growth in cell culture. J Virol 61, 829839.[Medline]
Samaniego, L. A., Neiderhiser, L. & DeLuca, N. A. (1998). Persistence and expression of the herpes simplex virus genome in the absence of immediate-early proteins. J Virol 72, 33073320.
Schang, L. M. & Jones, C. (1997). Analysis of bovine herpesvirus 1 transcripts during a primary infection of trigeminal ganglia of cattle. J Virol 71, 67866795.[Abstract]
Stow, N. D. & Stow, E. C. (1986). Isolation and characterization of a herpes simplex virus type 1 mutant containing a deletion within the gene encoding the immediate early polypeptide Vmw110. J Gen Virol 67, 25712585.[Abstract]
Van Sant, C., Hagglund, R., Lopez, P. & Roizman, B. (2001). The infected cell protein 0 of herpes simplex virus 1 dynamically interacts with proteasomes, binds and activates the cdc34 E2 ubiquitin-conjugating enzyme, and possesses in vitro E3 ubiquitin ligase activity. Proc Natl Acad Sci U S A 98, 88158820.
Winkler, M. T. C., Doster, A. & Jones, C. (1999). Bovine herpesvirus 1 can infect CD4+ T lymphocytes and induce programmed cell death during acute infection of cattle. J Virol 73, 86578668.
Winkler, M. T. C., Doster, A. & Jones, C. (2000). Persistence and reactivation of bovine herpesvirus 1 in the tonsils of latently infected calves. J Virol 74, 53375346.
Winkler, M. T. C., Doster, A., Sur, J.-H. & Jones, C. (2002). Analysis of bovine trigeminal ganglia following infection with bovine herpesvirus 1. Vet Microbiol 86, 139155.[CrossRef][Medline]
Wirth, U. V., Gunkel, K., Engels, M. & Schwyzer, M. (1989). Spatial and temporal distribution of bovine herpesvirus 1 transcripts. J Virol 63, 48824889.[Medline]
Wirth, U. V., Vogt, B. & Schwyzer, M. (1991). The three major immediate-early transcripts of bovine herpesvirus 1 arise from two divergent and spliced transcription units. J Virol 65, 195205.[Medline]
Wirth, U. V., Fraefel, C., Vogt, B., Vlek,
., Pa
es, V. & Schwyzer, M. (1992). Immediate-early RNA 2.9 and early RNA 2.6 of bovine herpesvirus 1 are 3' coterminal and encode a putative zinc finger transactivator protein. J Virol 66, 27632772.[Abstract]
Yao, F. & Schaffer, P. A. (1995). An activity specified by the osteosarcoma line U2OS can substitute functionally for ICP0, a major regulatory protein of herpes simplex virus type 1. J Virol 69, 62496258.[Abstract]
Zhang, Y. & Jones, C. (2001). The bovine herpesvirus 1 immediate-early protein (bICP0) associates with histone deacetylase 1 to activate transcription. J Virol 75, 95719578.
Zhang, Y., Zhou, J. & Jones, C. (2005). Identification of functional domains within the bICP0 protein encoded by bovine herpesvirus 1. J Gen Virol 86, 879886.
Received 25 January 2005;
accepted 17 March 2005.