Identification of a previously undescribed divergent virus from the Flaviviridae family in an outbreak of equine serum hepatitis.

Theiler's disease is an acute hepatitis in horses that is associated with the administration of equine blood products; its etiologic agent has remained unknown for nearly a century. Here, we used massively parallel sequencing to explore samples from a recent Theiler's disease outbreak. Metatranscriptomic analysis of the short sequence reads identified a 10.5-kb sequence from a previously undescribed virus of the Flaviviridae family, which we designate "Theiler's disease-associated virus" (TDAV). Phylogenetic analysis clusters TDAV with GB viruses of the recently proposed Pegivirus genus, although it shares only 35.3% amino acid identity with its closest relative, GB virus D. An epidemiological survey of additional horses from three separate locations supports an association between TDAV infection and acute serum hepatitis. Experimental inoculation of horses with TDAV-positive plasma provides evidence that several weeks of viremia preceded liver injury and that liver disease may not be directly related to the level of viremia. Like hepatitis C virus, the best characterized Flaviviridae species known to cause hepatitis, we find TDAV is capable of efficient parenteral transmission, engendering acute and chronic infections associated with a diversity of clinical presentations ranging from subclinical infection to clinical hepatitis.

Messenger RNA turnover and its regulation in herpesviral infection.

The ability to regulate cellular gene expression is a key aspect of the lifecycles of a diverse array of viruses. In fact, viral infection often results in a global shutoff of host cellular gene expression; such inhibition serves not only to ensure maximal viral gene expression without competition from the host for essential machinery and substrates but also aids in evasion of immune responses detrimental to successful viral replication and dissemination. Within the herpesvirus family, host shutoff is a prominent feature of both the alpha- and gamma-herpesviruses. Intriguingly, while both classes of herpesviruses block cellular gene expression by inducing decay of messenger RNAs, the viral factors responsible for this phenotype as well as the mechanisms by which it is achieved are quite distinct. However, data suggest that the host shutoff functions of alpha- and gamma-herpesviruses are likely achieved both through the activity of virally encoded nucleases as well as via modulation of cellular RNA degradation pathways. This review highlights the processes governing normal cellular messenger RNA decay and then details the mechanisms by which herpesviruses promote accelerated RNA turnover. Parallels between the viral and cellular degradation systems as well as the known interactions between viral host shutoff factors and the cellular RNA turnover machinery are highlighted.