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strategy deployed by the virus to direct the required functional changes in target
cells that ultimately promote viral survival and persistence in the host.
Introduction
HCMV is a species-specific β-herpesvirus found in more than 60% of the human
population (Mocarski et al. 2007). HCMV causes severe disease in immunocom-
promised individuals, where it is a major opportunistic pathogen in AIDS and
organ transplant patients, in congenitally infected neonates, and in cancer patients
undergoing chemotherapy (see the chapter by W. Britt, this volume). In the immu-
nocompetent host, HCMV causes mononucleosis (see the chapter by W. Britt, this
volume) and is associated with chronic human diseases such as atherosclerosis and
restenosis (Melnick et al. 1993; Speir et al. 1994; Waldman et al. 1997; Streblow
et al. 1999, 2001a) and some forms of cancer (Shen et al. 1993; Cobbs et al. 2002;
Soderberg-Naucler 2006).
A hallmark of HCMV infection is a broad cellular tropism in vivo that results in
the infection of most host organ tissues (Myerson et al. 1984; Sinzger and Jahn 1996;
Mocarski et al. 2007; see the chapter by C. Sinzger et al., this volume). HCMV patho-
genesis is a direct result of the infection of host organs and the resulting overt organ
disease (Sinzger and Jahn 1996; Mocarski et al. 2007). From an evolutionary stand-
point, the ability to infect multiple organs provides the virus access to multiple portals
of viral exit and, consequently, allows viral shedding in most human body fluids
(Mocarski et al. 2007). Broad cellular tropism necessitates that the virus possess a
strategy to productively infect a diverse array of cell types that have unique biochemi-
cal features. Regardless of the diversity of cells found in the human host, all cell types
utilize cellular signaling pathways as a means of cellular communication and appro-
priate response to their environment (Cooper and Hausman 2007). Thus, cellular sig-
naling from a general standpoint is a common thread among multiple cell types that,
if exploited correctly, would allow HCMV to transcend the differences among cell
types. Mechanistically, the exploitation of cellular signaling by the virus provides at
least one biological explanation for HCMV's broad tropism in vivo. Certainly viral
attachment to an infected cell surface is also a determinant of tropism (see the chapter
by C. Sinzger et al., this volume), but because this chapter focuses on the viral modu-
lation of cellular signaling, we will only discuss how cellular signaling can be
exploited by the virus to promote persistence and survival in a variety of host cell
types. Nevertheless, because we (Yurochko et al. 1995, 1997a; Yurochko and Huang
1999; Bentz and Yurochko, unpublished data) and others (Keay et al. 1995; Boyle et
al. 1999; Simmen et al. 2001; Compton et al. 2003; Wang et al. 2003; Boehme et al.
2004; Feire et al. 2004; Wang et al. 2005; Boehme et al. 2006) have strong evidence
that viral ligand-mediated signaling is stimulated by the same viral glycoproteins
responsible for viral attachment, fusion, and entry (Britt and Mach 1996), it is likely
that these two seemingly diverse mechanisms are intimately linked and together pro-
vide key control points for the infection of the host. We propose that cellular signal-
ing is a biological aspect exploited by HCMV during infection (from viral entry to
