title: The m4 gene of murine gammaherpesvirus modulates productive and latent infection in vivo.
abstract: Murine gammaherpesvirus 68 (MHV-68) infection of mice represents a viable small-animal model for the study of gammaherpesvirus pathogenesis. MHV-76 is a deletion mutant of MHV-68, which lacks four MHV-68-specific genes (M1 to M4) and eight viral tRNA-like sequences at the 5' end of the genome. These genes are implicated in latency and/or immune evasion. Consequently, MHV-76 is attenuated in the acute phase of in vivo infection with respect to MHV-68. Little is known about the role of M4 in viral infection, except that it is expressed as an immediate-early/early transcript during lytic replication of MHV-68 in vitro. To elucidate the contribution M4 makes to in vivo pathogenesis, we created a novel MHV-76 mutant (MHV-76inM4), in which the region of MHV-68 coding for M4 and accompanying putative promoter elements were inserted into the 5' region of the MHV-76 genome. The growth of MHV-76inM4 in vitro was indistinguishable from that of MHV-76 and MHV-68. However, virus titers from MHV-76inM4-infected BALB/c mice were significantly increased with respect to MHV-76 at early times in the lung. In addition, at days 17 and 21 postinfection, there was a significant elevation in latent viral load in splenocytes of MHV-76inM4-infected mice compared to MHV-76. Like MHV-76-infected mice, MHV-76inM4-infected mice display no evidence of overt splenomegaly, a finding characteristic of MHV-68 infection. M4 expression in vivo was detectable during productive infection in the lung and during the establishment of latency in the spleen, but in general M4 was not detectable during long-term latency (day 100 postinfection).
authors.affiliation: Laboratory for Clinical and Molecular Virology, University of Edinburgh, Summerhall, Edinburgh EH9 1QH, United Kingdom.
authors.forename: A C
authors.initials: AC
authors.lastname: Townsley
authors.forename: B M
authors.initials: BM
authors.lastname: Dutia
authors.forename: A A
authors.initials: AA
authors.lastname: Nash
mesh_terms: D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D005260:Female; D018142:Gammaherpesvirinae / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D015967:Gene Expression Regulation, Viral; D006566:Herpesviridae Infections / Q000503:physiopathology / Q000821:virology; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D014158:Transcription, Genetic; D014774:Virulence; D014775:Virus Activation; D017735:Virus Latency; D014779:Virus Replication
chemical_list: D017874:Immediate-Early Proteins