Pseudorabies virus (PRV) is a herpesvirus of swine, a member of the Alphaherpesvirinae subfamily, and the etiological agent of Aujeszky's disease. This review describes the contributions of PRV research to herpesvirus biology, neurobiology, and viral pathogenesis by focusing on (i) the molecular biology of PRV, (ii) model systems to study PRV pathogenesis and neurovirulence, (iii) PRV transsynaptic tracing of neuronal circuits, and (iv) veterinary aspects of pseudorabies disease. The structure of the enveloped infectious particle, the content of the viral DNA genome, and a step-by-step overview of the viral replication cycle are presented. PRV infection is initiated by binding to cellular receptors to allow penetration into the cell. After reaching the nucleus, the viral genome directs a regulated gene expression cascade that culminates with viral DNA replication and production of new virion constituents. Finally, progeny virions self-assemble and exit the host cells. Animal models and neuronal culture systems developed for the study of PRV pathogenesis and neurovirulence are discussed. PRV serves as a self-perpetuating transsynaptic tracer of neuronal circuitry, and we detail the original studies of PRV circuitry mapping, the biology underlying this application, and the development of the next generation of tracer viruses. The basic veterinary aspects of pseudorabies management and disease in swine are discussed. PRV infection progresses from acute infection of the respiratory epithelium to latent infection in the peripheral nervous system. Sporadic reactivation from latency can transmit PRV to new hosts. The successful management of PRV disease has relied on vaccination, prevention, and testing.

Molecular Biology of Pseudorabies Virus: Impact on Neurovirology and Veterinary Medicine

This review is a short update on the diversity of swine biomedical models and the importance of genomics in their continued development. The swine has been used as a major mammalian model for human studies because of the similarity in size and physiology, and in organ development and disease progression. The pig model allows for deliberately timed studies, imaging of internal vessels and organs using standard human technologies, and collection of repeated peripheral samples and, at kill, detailed mucosal tissues. The ability to use pigs from the same litter, or cloned or transgenic pigs, facilitates comparative analyses and genetic mapping. The availability of numerous well defined cell lines, representing a broad range of tissues, further facilitates testing of gene expression, drug susceptibility, etc. Thus the pig is an excellent biomedical model for humans. For genomic applications it is an asset that the pig genome has high sequence and chromosome structure homology with humans. With the swine genome sequence now well advanced there are improving genetic and proteomic tools for these comparative analyses. The review will discuss some of the genomic approaches used to probe these models. The review will highlight genomic studies of melanoma and of infectious disease resistance, discussing issues to consider in designing such studies. It will end with a short discussion of the potential for genomic approaches to develop new alternatives for control of the most economically important disease of pigs, porcine reproductive and respiratory syndrome (PRRS), and the potential for applying knowledge gained with this virus for human viral infectious disease studies.

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Advances in swine biomedical model genomics.

Herpesvirus assembly: An update

Budding events in herpesvirus morphogenesis.

Herpesvirus assembly: a tale of two membranes

We have obtained the complete DNA sequence of pseudorabies virus (PRV), an alphaherpesvirus also known as Aujeszky's disease virus or suid herpesvirus 1, using sequence fragments derived from six different strains (Kaplan, Becker, Rice, Indiana-Funkhauser, NIA-3, and TNL). The assembled PRV genome sequence comprises 143,461 nucleotides. As expected, it matches the predicted gene arrangement, genome size, and restriction enzyme digest patterns. More than 70 open reading frames were identified with homologs in related alphaherpesviruses; none were unique to PRV. RNA polymerase II transcriptional control elements in the PRV genome, including core promoters, splice sites, and polyadenylation sites, were identified with computer prediction programs. The correlation between predicted and experimentally determined transcription start and stop sites was excellent. The transcriptional control architecture is characterized by three key features: core transcription elements shared between genes, yielding divergent transcripts and a large number of coterminal transcripts; bifunctional transcriptional elements, yielding head-to-tail transcripts; and short repetitive sequences that could function as insulators against improperly terminated transcripts. Many of these features are conserved in the alphaherpesvirus subfamily and have important implications for gene array analyses.

https://jvi.asm.org/content/jvi/78/1/424.full.pdf

Complete, annotated sequence of the pseudorabies virus genome.

Envelope glycoprotein M (gM) and the complex formed by glycoproteins E (gE) and I (gI) are involved in the secondary envelopment of pseudorabies virus (PrV) particles in the cytoplasm of infected cells. In the absence of the gE-gI complex and gM, envelopment is blocked and capsids surrounded by tegument proteins accumulate in the cytoplasm (A. R. Brack, J. Dijkstra, H. Granzow, B. G. Klupp, and T. C. Mettenleiter, J. Virol. 73:5364-5372, 1999). Here we demonstrate by yeast two-hybrid analyses that the cytoplasmic domains of gE and gM specifically interact with the C-terminal part of the UL49 gene product of PrV, which represents a major tegument protein and which is homologous to VP22 of herpes simplex virus type 1. However, deletion of the UL49 gene from PrV had only minor effects on viral replication, and ultrastructural analyses of infected cells confirmed that virus maturation and egress, including secondary envelopment in the cytoplasm, were not detectably affected by the absence of UL49. Moreover, the UL49 gene product was shown to be dispensable for virion localization of gE and gM, and mutants lacking either gE or gM incorporated the UL49 protein efficiently into virus particles. In contrast, a PrV mutant with deletions of gE-gI and gM failed to incorporate the UL49 protein despite apparently unaltered intracytoplasmic UL49 expression. In summary, we describe specific interactions between herpesvirus envelope and tegument proteins which may play a role in secondary envelopment during herpesvirus virion maturation.

Christoph J. Hengartner

Papers

Molecular Biology of Pseudorabies Virus: Impact on Neurovirology and Veterinary Medicine

Complete, annotated sequence of the pseudorabies virus genome.

Physical Interaction between Envelope Glycoproteins E and M of Pseudorabies Virus and the Major Tegument Protein UL49

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