An essential role for gamma-herpesvirus latency-associated nuclear antigen homolog in an acute lymphoproliferative disease of cattle

作者：Palmeira Leonor; Sorel Oceane; Van Campe Willem; Boudry Christel; Roels Stefan; Myster Francoise; Reschner Anca; Coulie Pierre G; Kerkhofs Pierre; Vanderplasschen Alain; Dewals Benjamin G^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2013, 110(21): E1933-E1942.

DOI：10.1073/pnas.1216531110

• whole-genome transcriptomics
• peripheral T-cell lymphoma

Wildebeests carry asymptomatically alcelaphine herpesvirus 1 (AIHV-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. Where as 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 aWT virus. Together, these findings suggest that a latent infection is essential for MCF induction.

• 出版日期2013-5-21