Dissecting the host response to a gamma-herpesvirus

The murine gamma -herpesvirus 68 (MHV-68) provides a unique experimental mo del for dissecting immunity to large DNA viruses that persist ill B lymphoc ytes. The analysis is greatly facilitated by the availability of geneticall y disrupted (-/-) mice that lack key host-response elements, and by tile fa ct that MHV-68 is a lytic virus that can readily be manipulated for mutatio nal analysis. Tile mutant virus strategy is being used, for example, to cha racterize the part played in vivo by an MHV-68-encoded chemokine-binding pr otein that may ultimately find an application in human therapeutics. Experi ments with various -/- mice and monoclonal antibody depletion protocols hav e shown very clearly that type I interferons (IFNs) are essential for the e arly control of MHV-68 replication, while CD4(+) T cells producing IFN-gamm a function to limit the consequences of viral persistence. virus-specific C D8(+) effectors acting in the absence of the CD4+ subset seem initially to control the lytic phase in the lung following respiratory challenge, but ar e then unable to prevent the reactivation of replicative infection in epith elia and the eventual death of CD4(+) T-cell-deficient mice. This could ref lect tile fact that tile interaction between the CD8(+) T cells and the vir us-infected targets is partially compromised by the MHV-68 K3 protein, whic h inhibits antigen presentation by R IHC class I glycoproteins. Immunizatio n strategies focusing on the CD8+ T-cell response to epitopes expressed dur ing the lytic phase of MHV-68 infection call limit virus replication, but a re unable to prevent the establishment of latency. Other experiments with m utant viruses also suggest that there is a disconnection between lytic MHV- 68 infection and latency. The massive nonspecific immunoglobulin response a nd the dramatic expansion of V beta4(+) CD8(+) T cells, which is apparently MHC independent, could represent some sort of 'smoke screen' used by MHV-6 8 to subvert immunity. Although MHV-68 is neither Epstein-Barr virus nor hu man herpesvirus-8, tile results generated from this system suggest possibil ities that may usefully be addressed with these human pathogens. Perhaps ti le main lesson learned to date is that all the components or immunity are l ikely to be important for the control of these complex viruses.