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Adler et al. 2006). Endothelial cell infection of fibroblast-adapted, poorly endothe-
liotropic HCMV strains Merlin, Towne and AD169 were rescued by transient
expression of intact UL128, UL130 and UL131, respectively (Hahn et al. 2004;
Patrone et al. 2005). This suggests that loss of endothelial cell tropism during
fibroblast adaptation is frequently caused by alterations in this gene region. In con-
trast, it is still unclear whether this gene region also contributes to the variability in
endothelial cell tropism among naturally occurring HCMV isolates (Sinzger et al.
1999b), as a series of 34 clinical isolates appeared to contain intact copies of these
genes (Baldanti et al. 2006).
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 enve-
lope (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 vol-
ume). 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 repli-
cation 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 rep-
lication 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
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