Vaccine potential of a murine gammaherpesvirus-68 mutant deficient for ORF73

Fowler, Polly; Efstathiou, Stacey

doi:10.1099/vir.0.19760-0

Cited by 36 publications

(29 citation statements)

References 23 publications

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“…Consequently, the BoHV-4 ORF73-deleted strain could be a good candidate for the development of BoHV-4 as a vector in vaccinology. This hypothesis is further supported by an early study on the vaccine potential of a MHV-68 mutant deficient for ORF73 (Fowler & Efstathiou, 2004). …”

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

confidence: 51%

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 Vivosupporting

confidence: 51%

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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“…To circumvent these problems, several labs have explored vaccination strategies involving live attenuated viruses, taking advantage of the availability of mutant viruses that are incapable of establishing latency or that are capable of establishing a latent infection with various defects in reactivation (15)(16)(17)(18). The new finding that viral replication is not absolutely required for the establishment of latency has led to renewed interest in replicationdeficient mutants (12)(13)(14)19).…”

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confidence: 99%

A Replication-Deficient Murine γ-Herpesvirus Blocked in Late Viral Gene Expression Can Establish Latency and Elicit Protective Cellular Immunity

Kayhan

Yager

Lanzer

et al. 2007

The Journal of Immunology

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The human γ-herpesviruses, EBV and Kaposi’s sarcoma-associated herpesvirus, are widely disseminated and are associated with the onset of a variety of malignancies. Thus, the development of prophylactic and therapeutic vaccination strategies is an important goal. The experimental mouse γ-herpesvirus, γHV68 (or MHV-68), has provided an in vivo model for studying immune control of these persistent viruses. In the current studies, we have examined infectivity, immunogenicity, and protective efficacy following infection with a replication-deficient γHV68 blocked in late viral gene expression, ORF31STOP. The data show that ORF31STOP was able to latently infect B cells. However, the anatomical site and persistence of the infection depended on the route of inoculation, implicating a role for viral replication in viral spread but not the infectivity per se. Furthermore, i.p. infection with ORF31STOP elicited strong cellular immunity but a non-neutralizing Ab response. In contrast, intranasal infection was poorly immunogenic. Consistent with this, mice infected i.p. had enhanced control of both the lytic and latent viral loads following challenge with wild-type γHV68, whereas intranasal infected mice were not protected. These data provide important insight into mechanisms of infection and protective immunity for the γ-herpesviruses and demonstrate the utility of replication-deficient mutant viruses in direct testing of “proof of principal” vaccination strategies.

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“…Neither vaccination strategy reduced the level of latent virus in the mice long term. However, protection from the establishment of long-term latency by vaccination is theoretically possible, since infection with MHV-68 mutants which are unable to reactivate from or establish latency prevents residual latency after challenge with wild-type virus (4,21). Little is known concerning the effect of priming T-cell responses that target both lytic and persistent phases of the virus life cycle.…”

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confidence: 99%

T-Cell Responses to the M3 Immune Evasion Protein of Murid Gammaherpesvirus 68 Are Partially Protective and Induced with Lytic Antigen Kinetics

Obar¹,

Donovan²,

Crist³

et al. 2004

J Virol

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DNA vaccination with the M3 gene, encoding an immune evasion molecule expressed during both the acute lytic and persistent phases of murid gammaherpesvirus 68 infection, yielded a significantly lower titer of virus in the lung than controls. The protection seen was dependent on T cells, and we mapped an epitope recognized by CD8 T cells. The immune response to this epitope follows the same kinetics as lytic cycle antigens, despite the fact that this gene is expressed in both lytic and persistent stages of infection. This has important implications for our understanding of T-cell responses to putative latency-associated gammaherpesvirus proteins and how vaccination may improve control of these viruses.

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Vaccine potential of a murine gammaherpesvirus-68 mutant deficient for ORF73

Cited by 36 publications

References 23 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

A Replication-Deficient Murine γ-Herpesvirus Blocked in Late Viral Gene Expression Can Establish Latency and Elicit Protective Cellular Immunity

T-Cell Responses to the M3 Immune Evasion Protein of Murid Gammaherpesvirus 68 Are Partially Protective and Induced with Lytic Antigen Kinetics

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