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See detailAn essential role for gamma-herpesvirus latency-associated nuclear antigen homolog in an acute lymphoproliferative disease of cattle.
Palmeira, Leonor; Sorel, Océane ULg; Van Campe, Willem et al

in Proceedings of the National Academy of Sciences of the United States of America (2013)

Wildebeests carry asymptomatically alcelaphine herpesvirus 1 (AlHV-1), a gamma-herpesvirus inducing malignant catarrhal fever (MCF) to several ruminant species (including cattle). This acute and lethal ... [more ▼]

Wildebeests carry asymptomatically alcelaphine herpesvirus 1 (AlHV-1), a gamma-herpesvirus inducing malignant catarrhal fever (MCF) to several ruminant species (including cattle). This acute and lethal lymphoproliferative disease occurs after a prolonged asymptomatic incubation period after transmission. Our recent findings with the rabbit model indicated that AlHV-1 infection is not productive during MCF. Here, we investigated whether latency establishment could explain this apparent absence of productive infection and sought to determine its role in MCF pathogenesis. First, whole-genome cellular and viral gene expression analyses were performed in lymph nodes of MCF-developing calves. Whereas a severe disruption in cellular genes was observed, only 10% of the entire AlHV-1 genome was expressed, contrasting with the 45% observed during productive infection in vitro. In vivo, the expressed viral genes included the latency-associated nuclear antigen homolog ORF73 but none of the regions known to be essential for productive infection. Next, genomic conformation analyses revealed that AlHV-1 was essentially episomal, further suggesting that MCF might be the consequence of a latent infection rather than abortive lytic infection. This hypothesis was further supported by the high frequencies of infected CD8+ T cells during MCF using immunodetection of ORF73 protein and single-cell RT-PCR approaches. Finally, the role of latency-associated ORF73 was addressed. A lack of ORF73 did not impair initial virus replication in vivo, but it rendered AlHV-1 unable to induce MCF and persist in vivo and conferred protection against a lethal challenge with a WT virus. Together, these findings suggest that a latent infection is essential for MCF induction. [less ▲]

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See detailCis-acting inhibition of MHC class I-restricted epitope presentation by Alcelaphine herpesvirus 1 genome maintenance protein
Sorel, Océane ULg; Myster, Françoise ULg; Vanderplasschen, Alain ULg et al

Poster (2013, January 18)

γ-Herpesviruses persist as latent episomes in actively dividing lymphocytes. Their consequent need to express a viral genome maintenance protein (GMP) during latency presents a potential immune target ... [more ▼]

γ-Herpesviruses persist as latent episomes in actively dividing lymphocytes. Their consequent need to express a viral genome maintenance protein (GMP) during latency presents a potential immune target. However, the GMPs from several γ-herpesviruses have evolved related strategies to limit their own MHC class I epitope presentation to cytotoxic T lymphocytes (CTLs). Alcelaphine herpesvirus 1 (AlHV-1) is a γ-herpesvirus that persists asymptomatically in its natural host, the wildebeest. However, AlHV-1 transmission to a large number of susceptible ruminants, including cattle, results in the development of a lethal lymphoproliferative disease named malignant catarrhal fever (MCF). We recently observed that the AlHV-1 GMP-homologue encoded by ORF73 is highly expressed during MCF and that the impairment of its expression renders AlHV-1 unable to induce MCF. With its 1300 aa, AlHV-1 ORF73 is the largest γ-herpesvirus GMP described to date and contains a large acidic internal repeat region that could be involved in the cis-acting CTL evasion mechanism. Here, we sought to determine the CTL evasion properties of AlHV-1 ORF73. We first performed bioinformatic analyses to characterize the protein domains. Then, we used an in vitro assay to demonstrate that ORF73 severely limits the presentation at the cell surface of an MHC class I-restricted epitope linked to ORF73 in cis. These results suggest that AlHV-1 has developed mechanisms to evade cytotoxic anti-viral response during latency. The exact mechanisms explaining the presentation defect remain to be deciphered as well as the role of the cis-acting CTL evasion mechanism of ORF73 in the pathogenesis of MCF. [less ▲]

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See detailLa forme africaine du coryza gangreneux est une maladie lymphoproliférative létale causée par l’herpèsvirus alcélaphin 1
Myster, Françoise ULg; Sorel, Océane ULg; Palmeira, Leonor et al

in Virologie (2012), 16(5), 299-314

Les gammaherpèsvirus comprennent des virus pouvant induire des maladies lymphoprolifératives et des tumeurs. Ceux-ci peuvent également per- sister à long terme en l’absence de toute manifestation ... [more ▼]

Les gammaherpèsvirus comprennent des virus pouvant induire des maladies lymphoprolifératives et des tumeurs. Ceux-ci peuvent également per- sister à long terme en l’absence de toute manifestation pathologique chez leur hôte naturel. Parmi les gammaherpèsvirus, l’herpèsvirus alcélaphin 1 (AlHV-1) appartient au genre des Macavirus et infecte son hôte naturel, le gnou (Conno- chaetes spp.) de manière asymptomatique. Par ailleurs, lors de sa transmission à de nombreuses espèces sensibles appartenant à l’ordre des artiodactyles, l’AlHV- 1 induit une maladie lymphoproliférative létale dénommée forme africaine du coryza gangreneux (FACG). Le contrôle de cette maladie dans les régions où l’AlHV-1 est endémique est important et dépend directement de la compréhen- sion des mécanismes pathogéniques responsables de l’induction de la FACG. Le but de cette revue est de synthétiser les connaissances actuelles sur l’AlHV-1 et la FACG avec un intérêt particulier porté aux mécanismes par lesquels l’AlHV- 1 induit la maladie. Parmi les différents modèles pathogéniques, nous discuterons du rôle particulier de la latence virale sur base des données actuelles. Enfin, la relation évolutive entre le gnou, l’AlHV-1 et les espèces sensibles à la FACG sera abordée. [less ▲]

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See detailInvestigation on the Role of the Viral Semaphorin encoded by the A3 Gene of Alcelaphine Herpesvirus 1 in the Induction of Malignant Catarrhal Fever
Myster, Françoise ULg; Palmeira, Leonor ULg; Vanderplasschen, Alain ULg et al

Poster (2011, July)

Alcelaphine herpesvirus 1 (AlHV-1) is a gammaherpesvirus carried by wildebeest asymptomatically. AlHV-1 is however responsible for the development of malignant catarrhal fever (MCF) when cross-species ... [more ▼]

Alcelaphine herpesvirus 1 (AlHV-1) is a gammaherpesvirus carried by wildebeest asymptomatically. AlHV-1 is however responsible for the development of malignant catarrhal fever (MCF) when cross-species transmitted to a variety of ruminant susceptible species. Wildebeest-derived (WD)-MCF is a fatal lymphoproliferative and degenerative disease of ruminants. Experimentally, WD-MCF can be reproduced in rabbits. A3 ORF encodes a putative semaphorin homolog protein, named AlHV-sema. Semaphorins are secreted and membrane-associated proteins characterized by a conserved ‘Sema’ domain. Initially identified as guidance factors assisting axons pathfinding during neural development, semaphorins have been shown over the last decade to have significant functions in various processes of immunoregulation. Phylogenetic analyses revealed that AlHV-sema and mammals Sema7A have a common ancestor and that AlHV-Sema has evolved independently of other viral semaphorins. Further bioinformatics analyses demonstrated that AlHV-Sema and cellular Sema7A share a highly similar tridimensional structure. In order to investigate the role of AlHV-Sema in WD-MCF induction, we used the AlHV-1 BAC clone and produced a strain deleted for A3 and a revertant strain. The strain deleted for A3 replicated comparably to the wild-type parental strain in vitro. In vivo, rabbits infected with the strain deleted for A3 developed WD-MCF with a small but significant delay compared to those infected with the parental and revertant strains. Deletion of A3 did not affect the increase of viral genomic charge over time in peripheral blood and in lymph nodes at time of death and the major histopathological lesions were present in all groups. Though infection with wild-type and revertant strains resulted in the inversion of CD8 over CD4 ratio and increased IFN- production in lymphoid tissues at time of death, both parameters were significantly reduced after infection with the A3 deleted strain. Together, these results suggest that AlHV-Sema play a role in the host response to AlHV-1 infection. [less ▲]

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See detailEx vivo bioluminescent detection of Alcelaphine herpesvirus 1 infection during malignant catarrhal fever.
Dewals, Benjamin G ULg; Myster, Françoise ULg; Palmeira, Leonor ULg et al

in Journal of Virology (2011), 85(14), 6941-54

Alcelaphine herpesvirus 1 (AlHV-1), carried by wildebeest asymptomatically, causes malignant catarrhal fever (WD-MCF) when cross-species transmitted to a variety of susceptible species of the Artiodactyla ... [more ▼]

Alcelaphine herpesvirus 1 (AlHV-1), carried by wildebeest asymptomatically, causes malignant catarrhal fever (WD-MCF) when cross-species transmitted to a variety of susceptible species of the Artiodactyla order. Experimentally, WD-MCF can be reproduced in rabbits. WD-MCF is described as a combination of lymphoproliferation and degenerative lesions in virtually all organs and caused by unknown mechanisms. Recently, we demonstrated that WD-MCF is associated with the proliferation of CD8(+) cells supporting a latent type of infection in lymphoid tissues. Here, we investigated the macroscopic distribution of AlHV-1 infection using ex vivo bioluminescence imaging in rabbit to determine whether it correlates with the distribution of lesions in lymphoid and non-lymphoid organs. To reach that goal, a recombinant AlHV-1 strain was produced by insertion of a luciferase expression cassette (luc) in an intergenic region. In vitro, the reconstituted AlHV-1 luc(+) strain replicated comparably to the parental strain and luciferase activity was detected by bioluminescence imaging. In vivo, rabbits infected with the AlHV-1 luc(+) strain developed WD-MCF comparably to the parental wild-type strain with hyperthermia and increase of both CD8(+) T cells frequencies and viral genomic charge over time in peripheral blood mononuclear cells and in lymph nodes at time of euthanasia. Bioluminescent imaging revealed that AlHV-1 infection could be detected ex vivo in lymphoid organs but also in lung, liver and kidney during WD-MCF, demonstrating that AlHV-1 infection is prevalent in tissue lesions. Finally, we show that the infiltrating mononuclear leukocytes in non-lymphoid organs are mainly CD8(+) T cells and that latency is predominant during WD-MCF. [less ▲]

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See detailThe A3 gene of Alcelaphine herpesvirus 1 encodes a viral semaphorin that is non-essential for the induction of malignant catarrhal fever
Myster, Françoise ULg; Palmeira, Leonor ULg; Vanderplasschen, Alain ULg et al

Conference (2010, November)

Alcelaphine herpesvirus 1 (AlHV-1) is a γ-Herpesvirus carried by wildebeest asymptomatically. AlHV-1 is however responsible for the development of malignant catarrhal fever (MCF) when cross-species ... [more ▼]

Alcelaphine herpesvirus 1 (AlHV-1) is a γ-Herpesvirus carried by wildebeest asymptomatically. AlHV-1 is however responsible for the development of malignant catarrhal fever (MCF) when cross-species transmitted to a variety of ruminant susceptible species. Wildebeest-derived (WD)-MCF is a frequently fatal lymphoproliferative and degenerative disease of ruminants. Experimentally, WD-MCF can be reproduced in rabbits. The A3 open reading frame (ORF) of the AlHV-1 encodes a putative semaphorin homolog protein, thereafter named AlHV-sema. Semaphorins are secreted and membrane-associated proteins characterized by a conserved amino-terminal ‘Sema’ domain. Initially identified as guidance factors that assist axons pathfinding during neural development, semaphorins have been shown over the last decade to have significant functions in various processes of immunoregulation. Bioinformatics analyses revealed that AlHV-sema has a high homology to the cellular Sema7A. Besides its roles in neural development, Sema7A has been shown to play pivotal functions in the regulation of cytokine secretion and as a tumor suppressor. In order to investigate whether AlHV-Sema could play a role in the pathogenesis of WD-MCF, we used the AlHV-1 BAC clone and produced a strain deleted for A3 and a revertant strain. The strain deleted for A3 replicated comparably to the wild-type parental strain in vitro. In vivo, rabbits infected with the strain deleted for A3 developed WD-MCF similarly to that observed with the parental strain with both severely increased CD8+ T cell frequencies and viral genomic charge over time in peripheral blood and in lymph nodes at time of death, as well as indistinguishable histopathological lesions in lymphoid organs and in liver, lung and kidney. In conclusion, this study demonstrates that AlHV-sema is not essential for the induction of WD-MCF in rabbits. [less ▲]

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See detailEx vivo bioluminescent detection of alcelaphine herpesvirus 1 infection during malignant catarrhal fever induced in rabbits
Dewals, Benjamin G ULg; Myster, Françoise ULg; Massart, François et al

Poster (2009, December 11)

Alcelaphine herpesvirus 1 (AlHV-1), carried by wildebeest asymptomatically, causes malignant catarrhal fever (WD-MCF) when cross-species transmitted to a variety of susceptible species of the Artiodactyla ... [more ▼]

Alcelaphine herpesvirus 1 (AlHV-1), carried by wildebeest asymptomatically, causes malignant catarrhal fever (WD-MCF) when cross-species transmitted to a variety of susceptible species of the Artiodactyla order. Experimentally, WD-MCF can be reproduced in rabbits. The lesions observed are very similar to those described in natural host species. Recently, we demonstrated that WD-MCF induced by AlHV-1 in rabbits is associated with the proliferation of CD8+ cells supporting a latent type of infection. In the present study, we investigated whether the virus could be detected ex vivo in the tissues of rabbits developing WD-MCF. Taking advantage of the recent cloning of the AlHV-1 genome as a bacterial artificial chromosome (BAC), we produced a recombinant plasmid encoding a firefly luciferase (LUC) expression cassette inserted in a non-coding region of the AlHV-1 genome. In vitro, the reconstituted AlHV-1 LUC strain replicated comparably to the parental strain in permissive cells and was able to induce a bioluminescent signal. In vivo, rabbits infected with the AlHV-1 LUC strain developed WD-MCF similarly to the parental wild-type strain with hyperthermia, increased CD8/CD4 ratio and viral genomic charge over time in PBMC and in lymph nodes at time of death. To identify the presence of AlHV-1 infection ex vivo, various organs of infected rabbits developing WD-MCF were analysed by bioluminescent imaging. Luciferase activity could be detected macroscopically at the time of death in most of analyzed organs including lung, popliteal and mesenteric lymph nodes, spleen, liver, kidney and appendix. Infectious virus could be isolated following co-cultures of lymph node and permissive cells, and the isolated virus retained the ability to induce a bioluminescent signal. In conclusion, we produced an AlHV-1 LUC recombinant and we were able to detect the AlHV-1 infection ex vivo in many organs at the time of death. [less ▲]

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