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efficient infection cycle. In human diploid fibroblasts, gB and gH stimulate signal
transduction pathways required for viral entry (Wang et al. 2003, 2005; Feire et al.
2004), demonstrating that rapid signaling serves initially to stimulate entry. The
same pathways required for this essential first step in the infection process (the
activation of the EGFR kinase and Src via binding to EGFR and the integrins,
respectively) also rapidly induce transcription factors such as NFκ-B. In our model,
this induction is required for efficient transactivation of the MIEP and the produc-
tion of viral IE gene products (DeMeritt et al. 2004), as well as the later viral gene
classes (DeMeritt et al. 2006). It is likely that this facet of the viral biology, the
activation of required host cell factors (transcription factors, cell cycle regulators,
etc.) through the targeted specific activation of signal transduction pathways, is
repeated for other specific pathways documented to be activated during infection
of target cells. For example, additional transcription factors such as Sp1 are also
induced following viral binding to promote the transactivation of the MIEP
(Isomura et al. 2005; Yurochko et al. 1997a, 1997b). Because other signaling play-
ers such as the virion-associated CKII (Nogalski et al. 2007) and various tegument
proteins (Romanowski et al. 1997; Stamminger et al. 2002; Schierling et al. 2004;
Cantrell and Bresnahan 2006a; Feng et al. 2006; Munger et al. 2006; Saffert and
Kalejta 2006) also promote the efficient expression of the IE gene products, it
appears that multiple signaling pathways, although biochemically distinct, coordi-
nate their efforts to focus on a single goal for the virus such as the upregulation of
the MIEP and the initiation of the viral gene cascade. Other steps in the viral infec-
tion cycle are also essential to the infection process; thus it is likely that additional
viral-mediated signaling pathways converge on a common molecular outcome to
benefit the virus. An example is the role various tegument proteins and IE gene
products play in ensuring that the required cellular replicative enzymes are available
for viral replication (Castillo and Kowalik 2004).
Different cell types have distinct signaling capabilities, and even the same signal
transduction pathway can have divergent downstream consequences in different
cell types. Thus, we hypothesize that the viral regulation of signaling pathways will
have different outcomes in cells such as endothelial cells and monocytes, which are
critical cells for in vivo infection. We recently provided evidence for a unique two-
pronged strategy for hematogenous dissemination involving endothelial cells and
monocytes: (1) HCMV directly infects vascular endothelial cells (see references
within Bentz et al. 2006; Mocarski et al. 2007; C. Sinzger et al., this volume), which
in turn promotes naïve monocyte transendothelial migration and viral transfer to
these migrating monocytes (Bentz et al. 2006), and (2) HCMV directly infects
peripheral blood monocytes in order to promote their transendothelial migration
(Smith et al. 2004a). Following transendothelial migration, both pools of infected
monocytes differentiate into pro-inflammatory macrophages permissive for the
replication of the original input virus, even though the original undifferentiated
monocyte was not permissive for viral replication at the time of infection. The virus
initiates these functional changes in endothelial cells and monocytes through the
binding of viral glycoproteins to EGFR and cellular integrins and the resulting
modulation of downstream signaling cascades such as the PI(3)K and NFκ-B
