Natural history of murine gamma-herpesvirus infection

Murine gamma -herpesvirus 68 (MHV-68) is a natural pathogen of small rodent s and insectivores (mice, voles and shrews). The primary infection is chara cterized by virus replication in lung epithelial cells and the establishmen t of a latent infection in R lymphocytes. The virus is also observed to per sist in lung epithelial cells, dendritic cells and macrophages. Splenomegal y is observed two weeks after infection, in which there is a CD4(+) T-cell- mediated expansion of B and T-cells in the spleen. At three weeks post-infe ction an infectious mononuclcosis-like syndrome is observed involving a maj or expansion of V beta4(+)CD8(+) T cells. Later in the course of persistent infection, ca. 10% of mice develop lymphoproliferative disease characteriz ed as lymphomas of B-cell origin. The genome from MHV-68 strain g 2.4 has been sequenced and contains ca. 73 genes, the majority of which are collinear and homologous to other gamma -h erpesviruses. The genome includes cellular homologues for a complement-regu latory protein, Bcl-2, cyclin D and interleukin-8 receptor and a set of nov el genes M1 to M4. The function of these genes in the context of latent inf ections, evasion of immune responses and virus-mediated pathologies is disc ussed. Both innate and adaptive immune responses play an active role in limiting v irus infection. The absence of type I interferon (IFN) results in a lethal MHV-68 infection, emphasizing the central role of these cytokines at the in itial stages of infection. In contrast, type II IFN is not essential for ti le recovery from infection in the lung, but a failure of type II IFN recept or signalling results in the atrophy of lymphoid tissue associated with vir us persistence. Splenic atrophy appears to be the result of immunopathology , since in the absence of CD8(+) T cells no pathology occurs. CD8(+) T cell s play a major role in recovery from the primary infection, and also in reg ulating latently infected cells expressing tile M2 gene product. CD4(+) T c ells have a key role in surveillance against virus recurrences in the lung, in part mediated through 'help' in the genesis of neutralizing antibodies. In the absence of CD4(+) T cells, virus-specific CD8+ T cells are able to control the primary infection in the respiratory tract, yet surprisingly th e memory CD8(+) T cells generated are unable Co inhibit virus recurrences i n the lung. This could be explained in part by the observations that this v irus can downregulate major histocompatibility complex class I expression a nd also restrict inflammatory cell responses by producing a chemokine-bindi ng protein (M3 gene product). MHV-68 provides an excellent model to explore methods for controlling gamma -herprsvirus infection through vaccination and chemotherapy Vaccination wi th gp150 (a homologue of gp350 of Epstein-Barr virus) results in a reductio n in splenomegaly and virus latency but does not block replication in tile lung, nor the establishment of a latent infection. Even when lung virus inf ection is greatly reduced following the action of CD8(+) Tcells, induced vi a a prime-boost vaccination strategy, a latent infection is established. Po tent antiviral compounds such as the nucleoside analogue 2 ' deoxy-5-ethyl- beta-4 ' -thiouridine, which disrupts virus replication in vivo, cannot inh ibit the establishment of a latent infection. Clearly, devising strategics to interrupt the establishment of latent virus infections may well prove im possible with existing methods.