Cytopathic Effect of Replication

From histological examinations of liver at the peak of natural and experimental HDV infections, whether fulminant or nonfulminant, it has been concluded that HDV replication can be cytopathic and that this can occur independently of infiltrating lymphocytes (Gowans and Bonino 1993).

In contrast, for HDV replication in cultured cells the picture has been controversial (Lazinski and Taylor 1994b). In some cases, overexpression of no more than the delta protein has been sufficient to cause cell death (Chang et al. 2000; Gowans et al. 1991; Liu et al. 2001). Also, transient replication of the HDV genome has been shown to interfere with cell colony forming ability (Wang et al. 2001). In other cases, neither expression of HDAg nor replication of the HDV genome has been sufficient to induce detectable cell death (Lazinski and Taylor 1994b). In part, the variability of these results maybe due to a combination of two factors. First, most replication initiated in cultured cells involves no cell-to-cell spread, and second, HDV replication in cultured cells becomes self-limiting within days because of the accumulation of mutated forms of S-HDAg which no longer support HDV genome replication. Consistent with this explanation are studies of replication in a cell system with an unchanging source of S-HDAg (Sect. 3.1.3). In such studies, low levels of replication are not detectably cytotoxic and replication can be maintained for more than a year. However, induction of an increased level of genome replication causes cyto-pathic effectsdetectablewithin1 -2 days. The cellsstopgrowing,there isaspe-cific accumulation of cells in Gi/G0 phase and within 6 days virtually all the cells have become nonadherent and proceed to cell death (Chang et al. 2005).

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