infection in vzvo, the model differs from the arrangement found in normally infected hosts in important ways. First, the viral genome in these mice is integrated into the host genome and present in a linear, tandem repeat orientation, as opposed to its usual form in normal infections, in which the genomic template is a covalently closed, unit-length, episomal circle present in multiple copies. Second, despite the presence of an uninterrupted, greater-than-unit-length genome in the transgenic mouse, only one of the three major transcripts present in productive infections is synthesized, indicating that at least one essential factor is absent in the nonpermissive host for viral genome recognition or transcript initiation. Because pregenomic RNA is not produced, no viral nucleocapsids or particles are produced. This limits study of viral expression in these animals to the surface protein and precludes assessment of cytokine effects on viral assembly, secretion or uptake. Third, the transgenic mice are tolerant of surface antigen, by virtue of its production throughout development. Thus any models of immunopathogenesis must consider the relationship between primed transferred immune cell subpopulations and the tolerant native immune cells with which they interact. Despite these drawbacks, the transgenic model provides invaluable information on the direct and indirect role of antigen-stimulated immune cells in viral pathogenesis and regulation.
The effect of diminishing surface expression on clinical outcome remains to be established. Decreased surface antigen levels could lead to fewer viral particles, contributing to viral clearance. Alternatively, diminished display of envelope on the hepatocellular membrane may blunt immune recognition, predisposing to incomplete clearance and chronicity. Viruses such as herpes simplex virus exploit this latency to evade host detection, and HBV may employ a similar strategy in hosts with developing persistent infection. What is certain is that an increased knowledge of the complex way in which cytokines and viruses interact will aid development of effective therapeutic agents and prediction of the natural history of infection.