Genome Sequence of Bovine Herpesvirus 4, a Bovine
            <i>Rhadinovirus,</i>
            and Identification of an Origin of DNA Replication

Zimmermann, Wolfgang; Broll, Hermann; Ehlers, Bernhard; Buhk, Hans-Jörg; Rosenthal, André; Goltz, Michael

doi:10.1128/jvi.75.3.1186-1194.2001

Cited by 98 publications

(123 citation statements)

References 45 publications

(35 reference statements)

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“…BoHV-4: (i) has a less complex genome than other herpesviruses (Zimmermann et al, 2001); (ii) can accommodate large amounts of foreign genetic material (Gillet et al, 2005); (iii) can replicate in a broad range of host species both in vitro and in vivo, in contrast to most gammaherpesviruses (Thiry et al, 1992); and (iv) exhibits limited or no pathogenicity in natural and experimental hosts (Thiry et al, 1992). However, the property of BoHV-4 that allows establishment of latency and reactivation makes wild-type strains inappropriate for developing safe recombinant vectors.…”

Section: Bohv-4 Orf73 Is Essential For Virus Persistence In Vivomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Whilst some rhadinoviruses encode orthologues of ORF71 and/or ORF72, all rhadinoviruses encode an ORF73 orthologue. For example, bovine herpesvirus 4 (BoHV-4) encodes orthologues of ORF71 and ORF73, whereas ORF72 is absent (Zimmermann et al, 2001 pORF73 is the latency-associated nuclear antigen 1 (LANA-1) of HHV-8. LANA-1 associates with mitotic chromosomes to enable episome tethering during division of latently infected cells and its subsequent partitioning between daughter cells (Ballestas et al, 1999; Barbera et al, 2006;Ye et al, 2004).…”

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confidence: 99%

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Bovine herpesvirus 4 ORF73 is dispensable for virus growth in vitro, but is essential for virus persistence in vivo

Thirion

Machiels

Farnir

et al. 2010

Journal of General Virology

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ORF73 orthologues encoded by different rhadinoviruses have been studied extensively. These studies revealed that the ORF73 expression product (pORF73) is a multifunctional protein essential for latency that enables episome tethering to mitotic chromosomes and modulates cellular pathways implicated in growth and survival of latently infected cells. Comparison of pORF73 orthologues encoded by rhadinoviruses reveals important variations in amino acid sequence length and composition. Bovine herpesvirus 4 (BoHV-4) encodes by far the shortest ORF73 orthologue, with a size equivalent to only 22 % of that of the largest orthologues. The present study focused on determining whether BoHV-4 ORF73 is a bona fide gene and investigating whether it is essential for latency, as established for larger ORF73 orthologues. Our results demonstrate that BoHV-4 ORF73 is transcribed as immediate-early polycistronic mRNA together with ORF71. Using a BoHV-4 bacterial artificial chromosome clone, we produced a strain deleted for ORF73 and a revertant strain. Deletion of BoHV-4 ORF73 did not affect the capacity of the virus to replicate in vitro, but it prevented latent infection in vivo using a rabbit model. Interestingly, the strain deleted for ORF73 induced an anti-BoHV-4 humoral immune response comparable to that elicited by the wild type and revertant recombinants. Together, these results demonstrate that, despite its relatively small size, BoHV-4 ORF73 is a functional homologue of larger rhadinovirus ORF73 orthologues, and highlight the potential of ORF73 deletion for the development of BoHV-4 as a vector in vaccinology. INTRODUCTIONGammaherpesviruses, like all viruses in the family Herpesviridae, exhibit two distinct phases in their life cycle: lytic replication, characterized by a transcription programme in which immediate-early (IE), early (E) and late (L) genes are expressed successively; and latency, characterized by the maintenance of the viral genome as a nonintegrated episome and the expression of a limited number of viral genes and microRNAs (Cai et al., 2005;Roizman & Pellett, 2007;Sarid et al., 1998;Weck et al., 1999). Upon reactivation, latency shifts to lytic replication.The gammaherpesvirus human herpesvirus 8 (HHV-8, also termed KSHV for Kaposi's sarcoma-associated herpesvirus), is the prototype of the genus Rhadinovirus. During latency, HHV-8 expresses three main ORFs: ORF71, ORF72 and ORF73 (Sarid et al., 1998(Sarid et al., , 1999. ORF71 and ORF72 encode viral homologues of cellular FLIP (Thome et al., 1997) and D cyclin (Li et al., 1997), respectively. ORF71 and ORF72 are expressed together with ORF73 as a polycistronic mRNA (Dittmer et al., 1998;Talbot et al., 1999). Whilst some rhadinoviruses encode orthologues of ORF71 and/or ORF72, all rhadinoviruses encode an ORF73 orthologue. For example, bovine herpesvirus 4 (BoHV-4) encodes orthologues of ORF71 and ORF73, whereas ORF72 is absent (Zimmermann et al., 2001 pORF73 is the latency-associated nuclear antigen 1 (LANA-1) of HHV-8. LANA-1 associates with mitotic chrom...

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Section: Bohv-4 Orf73 Is Essential For Virus Persistence In Vivomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Bovine herpesvirus 4 ORF73 is dispensable for virus growth in vitro, but is essential for virus persistence in vivo

Thirion

Machiels

Farnir

et al. 2010

Journal of General Virology

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“…The BoHV-4 genome is estimated to encode at least 79 open reading frames (ORFs) (42,59). Like all herpesviruses, BoHV-4 virions are composed of a large (diameter Ͼ 100 nm) icosahedral nucleocapsid, which is assembled in the nucleus from at least eight different conserved proteins (1).…”

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confidence: 99%

Proteomic Characterization of Bovine Herpesvirus 4 Extracellular Virions

Lété

Palmeira

Leroy

et al. 2012

J Virol

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cGammaherpesviruses are important pathogens in human and animal populations. During early events of infection, these viruses manipulate preexisting host cell signaling pathways to allow successful infection. The different proteins that compose viral particles are therefore likely to have critical functions not only in viral structures and in entry into target cell but also in evasion of the host's antiviral response. In this study, we analyzed the protein composition of bovine herpesvirus 4 (BoHV-4), a close relative of the human Kaposi's sarcoma-associated herpesvirus. Using mass spectrometry-based approaches, we identified 37 viral proteins associated with extracellular virions, among which 24 were resistant to proteinase K treatment of intact virions. Analysis of proteins associated with purified capsid-tegument preparations allowed us to define protein localization. In parallel, in order to identify some previously undefined open reading frames, we mapped peptides detected in whole virion lysates onto the six frames of the BoHV-4 genome to generate a proteogenomic map of BoHV-4 virions. Furthermore, we detected important glycosylation of three envelope proteins: gB, gH, and gp180. Finally, we identified 38 host proteins associated with BoHV-4 virions; 15 of these proteins were resistant to proteinase K treatment of intact virions. Many of these have important functions in different cellular pathways involved in virus infection. This study extends our knowledge of gammaherpesvirus virions composition and provides new insights for understanding the life cycle of these viruses.

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“…1). The highest percentages of identity (70 and 75 %, respectively) were found with a ruminant gammaherpesvirus, the bovine herpesvirus 4 (BoHV-4), which is a member of the genus Rhadinovirus (Zimmermann et al, 2001). The viruses from which these two sequences originated were therefore tentatively named SbarRHV-1 and BbabRHV-1, respectively (Table 1).…”

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confidence: 99%

Novel herpesviruses of Suidae: indicators for a second genogroup of artiodactyl gammaherpesviruses

Ehlers

Lowden

2004

Journal of General Virology

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Five novel herpesviruses were identified in suid species from Africa (common warthog, Phacochoerus africanus) and South-East Asia (bearded pig, Sus barbatus; babirusa, Babyrousa babyrussa) by detection and analysis of their DNA polymerase genes. Three of the novel species, P. africanus cytomegalovirus 1, P. africanus lymphotropic herpesvirus 1 (PafrLHV-1) and S. barbatus lymphotropic herpesvirus 1 (SbarLHV-1), were closely related to known beta-(porcine cytomegalovirus) and gammaherpesviruses [porcine lymphotropic herpesvirus (PLHV) 1 and 3] of domestic pigs. In contrast, two novel species, S. barbatus rhadinovirus 1 (SbarRHV-1) and Babyrousa babyrussa rhadinovirus 1 (BbabRHV-1), were more closely related to a ruminant gammaherpesvirus, bovine herpesvirus 4 (BoHV-4), than to the porcine gammaherpesviruses PLHV-1, -2, -3, PafrLHV-1 and SbarLHV-1. SbarRHV-1, BbabRHV-1 and BoHV-4 were therefore tentatively assigned to a novel genogroup of artiodactyl gammaherpesviruses. This latter genogroup may also contain an as yet undiscovered gammaherpesvirus of domestic pigs, thereby adding a concern to their use in xenotransplantation.Domestic pigs (Sus scrofa) have been proposed as organ donors for xenotransplantation. A significant potential hazard and safety issue in xenotransplant patients is the transmission of porcine viruses (Auchincloss & Sachs, 1998;O'Connell et al., 2000;Onions et al., 2000). Porcine herpesviruses are of particular concern since human herpesviruses, predominantly cytomegalovirus and Epstein-Barr virus (EBV), are associated with severe disease in allotransplantation (Ferry & Harris, 1994;van Zanten et al., 1998). Furthermore, herpesviruses are often inapparent in their natural hosts, but result in severe disease after infection of foreign hosts. To illustrate, the B herpesvirus causes only a benign infection in rhesus monkeys but induces fatal encephalitis in humans (Eberle & Hilliard, 1995). Another example is ovine herpesvirus 2 (OvHV-2). This virus causes only a benign infection in sheep, yet results in a fatal malignant catarrhal fever in cattle and pigs (Albini et al., 2003). Consequently, considerable efforts are under way to produce experimental donor pigs free of a number of known swine microorganisms (Fishman, 1994;Tucker et al., 2002).We recently reported the discovery of three porcine gammaherpesviruses in S. scrofa. Due to their lymphotropism, they were named porcine lymphotropic herpesviruses 1, 2 and 3 (PLHV-1, -2, -3). PLHV-1 and -3 and PLHV-2 have been found to be highly prevalent in domestic and feral pig populations, respectively (Ehlers et al., 1999b;Ulrich et al., 1999;Chmielewicz et al., 2003a). Evidence for the pathogenic potential of PLHV-1 was obtained using a porcine model of haematopoietic stem cell transplantation. This virus induces a fatal lymphoproliferative disorder resembling human post-transplant lymphoproliferative disease (PTLD), which occurs predominantly after liver and bone marrow allotransplantation (Huang et al., 2001). While human PTLD is frequently associate...

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Genome Sequence of Bovine Herpesvirus 4, a Bovine Rhadinovirus, and Identification of an Origin of DNA Replication

Cited by 98 publications

References 45 publications

Bovine herpesvirus 4 ORF73 is dispensable for virus growth in vitro, but is essential for virus persistence in vivo

Bovine herpesvirus 4 ORF73 is dispensable for virus growth in vitro, but is essential for virus persistence in vivo

Proteomic Characterization of Bovine Herpesvirus 4 Extracellular Virions

Novel herpesviruses of Suidae: indicators for a second genogroup of artiodactyl gammaherpesviruses

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