Analysis of a novel strain of murine gammaherpesvirus reveals a genomic locus important for acute pathogenesis.
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.
Macrae
A I
AI
Laboratory for Clinical and Molecular Virology, The University of Edinburgh, Edinburgh EH9 1QH, United Kingdom.
Dutia
B M
BM
Milligan
S
S
Brownstein
D G
DG
Allen
D J
DJ
Mistrikova
J
J
Davison
A J
AJ
Nash
A A
AA
Stewart
J P
JP
D000818:Animals; D015139:Blotting, Southern; D002460:Cell Line; D004279:DNA, Viral / Q000032:analysis; D018142:Gammaherpesvirinae / Q000235:genetics* / Q000472:pathogenicity; D017353:Gene Deletion; D005814:Genes, Viral; D006566:Herpesviridae Infections / Q000473:pathology / Q000821:virology*; D008168:Lung / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009115:Muridae; D014657:Vasculitis / Q000473:pathology; D017735:Virus Latency; D014781:Viscera / Q000821:virology
D004279:DNA, Viral