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Journal of Virology, June 2001, p. 5315-5327, Vol. 75, No. 11
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.11.5315-5327.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Analysis of a Novel Strain of Murine Gammaherpesvirus Reveals a Genomic Locus Important for Acute Pathogenesis

Alastair I. Macrae,1 Bernadette M. Dutia,1 Steven Milligan,2 David G. Brownstein,1 Deborah J. Allen,1 Jela Mistrikova,3 Andrew J. Davison,2 Anthony A. Nash,1 and James P. Stewart1,*

Laboratory for Clinical and Molecular Virology, The University of Edinburgh, Edinburgh EH9 1QH,1 and MRC Virology Unit, Institute of Virology, Glasgow G11 5JR,2 United Kingdom, and Department of Microbiology and Virology, Faculty of Natural Sciences, Comenius University, 842 15 Bratislava, Slovak Republic3

Received 22 December 2000/Accepted 1 March 2001

Infection of mice by murine gammaherpesvirus 68 (MHV-68) is an excellent small-animal model of gammaherpesvirus pathogenesis in a natural host. We have carried out comparative studies of another herpesvirus, murine herpesvirus 76 (MHV-76), which was isolated at the same time as MHV-68 but from a different murid host, the yellow-necked mouse (Apodemus flavicollis). Molecular analyses revealed that the MHV-76 genome is essentially identical to that of MHV-68, except for deletion of 9,538 bp at the left end of the unique region. MHV-76 is therefore a deletion mutant that lacks four genes unique to MHV-68 (M1, M2, M3, and M4) as well as the eight viral tRNA-like genes. Replication of MHV-76 in cell culture was identical to that of MHV-68. However, following infection of mice, MHV-76 was cleared more rapidly from the lungs. In line with this, there was an increased inflammatory response in lungs with MHV-76. Splenomegaly was also significantly reduced following MHV-76 infection, and much less latent MHV-76 was detected in the spleen. Nevertheless, MHV-76 maintained long-term latency in the lungs and spleen. We utilized a cosmid containing the left end of the MHV-68 genome to reinsert the deleted sequence into MHV-76 by recombination in infected cells, and we isolated a rescuant virus designated MHV-76(cA8+)4 which was ostensibly genetically identical to MHV-68. The growth properties of the rescuant in infected mice were identical to those of MHV-68. These results demonstrate that genetic elements at the left end of the unique region of the MHV-68 genome play vital roles in host evasion and are critical to the development of splenic pathology.

* Corresponding author. Mailing address: Laboratory for Clinical and Molecular Virology, The University of Edinburgh, Summerhall, Edinburgh EH9 1QH, United Kingdom. Phone: 44 131 650 7939. Fax: 44 131 650 6511. E-mail: james.stewart{at}ed.ac.uk.

Journal of Virology, June 2001, p. 5315-5327, Vol. 75, No. 11
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.11.5315-5327.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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