Critical Events for Replication in Various Cell Types

Regarding the replication steps critical for successful infection of various cell types, interstrain comparisons in endothelial cells showed a particular role of initial postpenetration events. The efficiency of nuclear translocation of incoming virions and subsequent delivery of the viral genome to the nucleus of penetrated endothe-lial cells is very low with fibroblast-adapted strains (Sinzger et al. 2000), and a similar block occurs in monocyte-derived macrophages (Sinzger et al. 2006). In contrast, these steps are strain-independent in fibroblasts. The demonstration that pUL128-131 are part of glycoprotein complexes with gH and gL in the virion envelope (Wang and Shenk 2005b; Adler et al. 2006) fit well with the finding that endothelial cell tropism of HCMV is determined during entry, as gH is known to be involved in fusion events (see also the chapter by M.K. Isaacson et al., this volume). The particular importance of initial events is further emphasized by recent data suggesting infection of endothelial cells by an endocytic route, in contrast to direct fusion at the plasma membrane of fibroblasts (Sinzger 2008). It appears that, unlike previously assumed (Bodaghi et al. 1999), endocytosis of HCMV in endothelial cells is not necessarily an abortive pathway (Fig. 3). For Epstein Barr virus, different gH/gL complexes are engaged in different cell types, leading either to direct fusion in lymphocytes or endocytosis in epithelial cells. Interestingly, a cell-type-dependent cell-cell fusion activity induced by gH-gL complexes was found in a transient expression system (Kinzler and Compton 2005).

The susceptibility of other cell types may be regulated at later steps of the replication cycle. For example, infection of polymorphonuclear leukocytes is aborted after onset of IE gene expression (Grefte et al. 1994), independent of the virus strain. The exact nature of this block of progression toward the early phase of replication is unknown. In trophoblast cells, hepatocyte or macrophage HCMV can proceed through all phases of the replication cycle, formation and/or release of viral progeny. However, the production of progeny is up to 1,000-fold less efficient than in fibroblasts (Halwachs-Baumann et al. 1998; Sinzger et al. 1999a, 2006) and again the factors contributing to these differences in productivity are not known.

In conclusion, genes UL128-131 classified as nonessential in fibroblast cultures have been shown to contribute to interstrain differences regarding infection of

Fig. 3 Hypothetical mechanism mediating interstrain differences in endothelial cell tropism. While all HCMV strains can release their capsids into fibroblasts by direct fusion of their envelope with the plasma membrane, cell type differences are assumed for viral entry into endothelial cells. Both highly endotheliotropic and poorly endotheliotropic strains are internalized by endocytosis, but only highly endotheliotropic can escape from endocytic vesicles and release their capsid into the cytoplasm

Fig. 3 Hypothetical mechanism mediating interstrain differences in endothelial cell tropism. While all HCMV strains can release their capsids into fibroblasts by direct fusion of their envelope with the plasma membrane, cell type differences are assumed for viral entry into endothelial cells. Both highly endotheliotropic and poorly endotheliotropic strains are internalized by endocytosis, but only highly endotheliotropic can escape from endocytic vesicles and release their capsid into the cytoplasm endothelial cells, epithelial cells and macrophages. As the respective proteins are structural components of the envelope of virion particles, it is not unexpected that they exert their effects on the level of viral entry. The cellular counterparts mediating the cell-type-specificity of these virion components are to be defined.

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