Transcriptome profile of murine gammaherpesvirus-68 lytic infection

Ebrahimi, Bahram; Dutia, Bernadette M.; Roberts, Kim L.; Garcı́a-Ramı́rez, José J.; Dickinson, Paul; Stewart, James P.; Ghazal, Peter; Roy, Douglas; Nash, Anthony

doi:10.1099/vir.0.18639-0

Cited by 116 publications

(125 citation statements)

References 36 publications

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“…2a). The expression of BoHV-4 ORF73 as an IE gene is consistent with earlier reports describing the expression of ORF73 orthologues encoded by rhadinoviruses early after infection (Ebrahimi et al, 2003;Martinez-Guzman et al, 2003;Sarid et al, 1999). …”

supporting

confidence: 80%

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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supporting

confidence: 80%

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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“…It appears paradoxical that M2-specific CD8 T cells are more cytolytic than ORF65-specific T cells as the latter would be expected to encounter Ag more often during latent infection. However ORF65 is a late protein, expressed only after viral DNA replication has occurred (29,30). Therefore it is likely that cells reactivating from latency may be killed by T cells specific for early or immediate early gene products before ORF65 is expressed.…”

Section: Discussionmentioning

confidence: 99%

Different Functional Capacities of Latent and Lytic Antigen-Specific CD8 T Cells in Murine Gammaherpesvirus Infection

Obar

Crist

Gondek

et al. 2004

The Journal of Immunology

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Gammaherpesviruses can persist in the host in the face of an aggressive immune response. T cells recognize Ags expressed in both the productive and latent phases of the virus life cycle, however little is known about their relative roles in the long-term control of the infection. In this study we used the murine gammaherpesvirus 68 model system to investigate the relative properties of CD8 T cells recognizing lytic and latent viral Ags. We report that the CD8 T cell response to lytic phase epitopes is maximal in the lungs of infected mice at ∼10 days postinfection, and is of progressively lesser magnitude in the mediastinal lymph nodes and spleen. In contrast, the CD8 T cell response to the latent M2 protein is maximal at ∼19 days postinfection and is most prominent in the spleen, then progressively less in the mediastinal lymph node and the lung. Latent and lytic Ag-specific CD8 T cells had markedly different cell surface phenotypes during chronic infection, with latent Ag-specific cells being predominantly CD62Lhigh or CD43 (1B11)high. Lytic Ag-specific T cells had significantly lower expression of these markers. Importantly, latent but not lytic Ag-specific T cells could kill target cells rapidly in vivo during the chronic infection. These two different sets of CD8 T cells also responded differentially to IL-7, a cytokine involved in T cell homeostasis and the maintenance of T cell memory. These data have important implications for our understanding of immunological control during chronic gammaherpesvirus infections.

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“…MHV-68 M3 protein, encoded by early-late lytic gene, is expressed continually during lytic infection, during the establishment of latent infection, and during latency in vivo (Simas et al, 1999;Ebrahimi et al, 2003). M3 protein is predicted to play a role in the establishment of latency by indirect protection of latently infected B cells during lytic infection of macrophages and dendritic cells (Flaño et al, 2000;Marques et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Soluble M3 proteins of murine gammaherpesviruses 68 and 72 expressed in Escherichia coli: analysis of chemokine-binding properties

Matuskova¹,

Pančík²,

Štibrániová³

et al. 2015

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Summary. -M3 protein of murine gammaherpesvirus 68 (MHV-68) was identifi ed as a viral chemokinebinding protein 3 (vCKBP-3) capable to bind a broad spectrum of chemokines and their receptors. During both acute and latent infection MHV-68 M3 protein provides a selective advantage for the virus by inhibiting the antiviral and infl ammatory response. A unique mutation Asp307Gly was identifi ed in the M3 protein of murine gammaherpesvirus 72 (MHV-72), localized near chemokine-binding domain. Study on chemokine-binding properties of MHV-72 M3 protein purifi ed from medium of infected cells implied reduced binding to some chemokines when compared to MHV-68 M3 protein. It was suggested that the mutation in the M3 protein might be involved in the attenuation of immune response to infection with MHV-72. Recently, Escherichia coli cells were used to prepare native recombinant M3 proteins of murine gammaherpesviruses 68 and 72 (Pančík et al., 2013). In this study, we assessed the chemokine-binding properties of three M3 proteins prepared in E. coli Rosetta-gami 2 (DE3) cells, the full length M3 protein of both MHV-68 and MHV-72 and MHV-68 M3 protein truncated in the signal sequence (the fi rst 24 aa). Th ey all displayed binding activity to human chemokines CCL5 (RANTES), CXCL8 (IL-8), and CCL3 (MIP-1α). Th e truncated MHV-68 M3 protein had more than twenty times reduced binding activity to CCL5, but only about fi ve and three times reduced binding to CXCL8 and CCL3 when compared to its full length counterpart. Binding of the full length MHV-72 M3 protein to all chemokines was reduced when compared to MHV-68 M3 protein. Its binding to CCL5 and CCL3 was reduced over ten and seven times. However, its binding to CXCL8 was only slightly reduced (64.8 vs 91.8%). Th ese data implied the signifi cance of the signal sequence and also of a single mutation (at aa 307) for effi cient M3 protein binding to some chemokines.

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Transcriptome profile of murine gammaherpesvirus-68 lytic infection

Cited by 116 publications

References 36 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

Different Functional Capacities of Latent and Lytic Antigen-Specific CD8 T Cells in Murine Gammaherpesvirus Infection

Soluble M3 proteins of murine gammaherpesviruses 68 and 72 expressed in Escherichia coli: analysis of chemokine-binding properties

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