Herpesvirus disease pathogenesis is closely linked to host immune status. Murine gammaherpesvirus 68 (?HV68) provides a model for studying the outcome of chronic gammaherpesvirus infection in the immunocompetent versus immunodeficient host. ?HV68 infection of a wild-type mouse results in a limited, acute infection at the site of inoculation, followed by latent, disseminated infection in a variety of tissues and cell types. Although wild-type mice rarely display any virus-related pathology, interferon-gamma receptor- deficient hosts (IFN?R-/-) develop potentially lethal, systemic inflammatory disease. This immune-mediated pathology consists of multi-organ fibrotic tissue damage and vasculitis, associated with chronic reactivation of latent virus and persistent replication. Interestingly, many features of this disease are absent during chronic infection with a ?HV68 mutant lacking the antigen encoded by the M1 open reading frame (ORF) - even though this mutant virus is not impaired for either acute replication or establishment of a latent infection. The M1 antigen, which bears sequence homology to some pox virus serpins (although it lacks critical catalytic residues) and to the ?HV68 secreted high affinity chemokine binding protein M3, has been shown to regulate ?HV68 reactivation from latency. The mechanism by which M1 exerts this effect, and the extent of immune system involvement, is unknown. Throughout the course of latency, the ?HV68 antiviral response is not appreciably stimulated with one notable exception - the significant expansion of V24+ CD8+ T cells. We have recently shown that expression of the M1 antigen is required for this response. This application aims to study the potentially novel mechanism(s) by which the ?HV68 M1 gene product induces V24+ T cell activity, perhaps to self-limit reactivation from latency through expression of IFN-?, and the role such T cells might play in mediating chronic disease in an immunocompromised host. The following 3 aims are proposed:
Aim 1 : Characterize M1 transcript structure(s) and regulation of M1 gene expression.
Aim 2 : Define the mechanism of M1-induced V24+ T cell activation and its influence on T cell function.
Aim 3 : Define the role of M1 and V24+ T cells in regulating ?HV68 reactivation, latency, and virus-induced systemic inflammatory disease. ? ? ?
