Malignant catarrhal fever (MCF) is an often lethal infection of many species in the order Artiodactyla. It is caused by members of the MCF virus group within Gammaherpesvirinae. MCF is a worldwide problem and has a significant economic impact on highly disease-susceptible hosts, such as cattle, bison, and deer. Several epidemiologic forms of MCF, defined by the reservoir ruminant species from which the causative virus arises, are recognized. Wildebeest-associated MCF (WA-MCF) and sheep-associated MCF (SA-MCF) are the most prevalent and well-studied forms of the disease. Historical understanding of MCF is largely based on WA-MCF, in which the causative virus can be propagated in vitro. Characterization of SA-MCF has been constrained because the causative agent has never been successfully propagated in vitro. Development of molecular tools has enabled more definitive studies on SA-MCF. The current understanding of MCF, including its etiological agents, epidemiology, pathogenesis, and prevention, is the subject of the present review.

Ovine herpesvirus 2 (OvHV-2), the major causative agent of malignant catarrhal fever in ruminant species worldwide, has never been propagated in vitro. Using real-time PCR, a striking, short-lived, peak of viral DNA, ranging from 10 5 to over 10 8 copies/2 g of DNA, was detected in nasal secretions from over 60.7% of adolescent sheep (n ‫؍‬ 56) at some point during the period from 6 to 9 months of age. In contrast, only about 18% of adult sheep (n ‫؍‬ 33) experienced a shedding episode during the study period. The general pattern of the appearance of viral DNA in nasal secretions was a dramatic rise and subsequent fall within 24 to 36 h, implying a single cycle of viral replication. These episodes occurred sporadically and infrequently, but over the 3-month period most of the 56 lambs (33, or 60.7%) experienced at least one episode. No corresponding fluctuations in DNA levels were found in either peripheral blood leukocytes or plasma. In a DNase protection assay, complete, enveloped OvHV-2 virions were demonstrated in the nasal secretions of all sheep examined during the time when they were experiencing an intense shedding episode. OvHV-2 infectivity in nasal secretions was also demonstrated by aerosolization of the secretions into OvHV-2-negative sheep. The data herein show that nasal shedding is the major mode of OvHV-2 transmission among domestic sheep and that adolescents represent the highest risk group for transmission.

The cleavage and packaging of newly synthesized herpesvirus DNA is a highly conserved process occurring late in viral replication. During herpesvirus infection, double-stranded viral DNA genomes accumulate in cell nuclei as head-to-tail concatemers which are subsequently cleaved into single genome lengths and packaged into preformed viral capsids (reviewed in reference 19). Six genes of herpes simplex virus type 1 (HSV-1) are known to be essential for this process, namely, U L 6, U L 15, U L 17, U L 28, U L 32, and U L 33. In cells infected with viruses individually lacking these genes, capsids appear normal and are readily detected, but viral DNA is neither cleaved nor packaged (2,3,5,9,12,25,26,30,31,35,37,(40)(41)(42)44).The cleavage and packaging process of herpesviruses is believed to be similar to that employed by double-stranded DNA bacteriophages; consequently, it is useful to consider the mechanisms used by these bacteriophages as a model for the cleavage and packaging events employed by herpesviruses. Such models propose a central role for the viral "terminase," a complex of at least two proteins that (i) binds the viral DNA and links it with the empty viral capsid (HSV-1) or prohead (bacteriophages); (ii) cleaves the viral DNA at precise internal sites, resulting in the separation of unit-length genomes from concatameric DNA; and (iii) hydrolyzes ATP, providing the energy required to drive the DNA into the capsid (reviewed in reference 10). With this paradigm in mind, efforts have been expended to identify herpesvirus gene products that perform functions expected of the viral terminase, especially DNA binding, ATP hydrolysis, and at least transient association with capsids.There is a growing body of both direct and indirect evidence suggesting that the U L 15 and U L 28 gene products comprise two subunits of the HSV-1 terminase. The U L 28 gene product has been shown to bind specifically to the HSV-1 DNA sequence pac1, which is found in the a sequence of the genome and is known to be essential for the generation of correct genomic termini (4, 38). The U L 15 protein has been hypothesized to hydrolyze ATP, based on limited homology with a putative nucleotide binding motif comprised of Walker boxes A and B within gp17, the larger subunit of the T4 bacteriophage terminase (15). Although the ATPase activity of the U L 15 protein has yet to be directly demonstrated, a mutation within the Walker box precludes viral DNA cleavage and packaging (46). The U L 28 and U L 15 proteins have also been shown to interact in transient-expression assays (1,22,23,45) and in coimmunoprecipitation experiments using nuclear extracts of infected cells (23).This paper describes the isolation of a protein complex consisting of the U L 28, U L 15, and U L 33 proteins by immunoprecipitation from lysates of infected cells. This suggests for the first time that the U L 33 gene product may function as a third subunit of the putative viral terminase. MATERIALS AND METHODS Cells and viruses.Vero and HEp-2 cells and transformed cell l...

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