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recognition of the mRNA's 5′-cap, is controlled through reversible phosphorylation of
the eucaryotic initiation factor (eIF) 4E-binding protein (4E-BP) (reviewed in Mamane
et al. 2006). This will be discussed in detail below in Sect. 3.
Although inhibition of translation may permit the cell to recover from stress, it
would not benefit HCMV replication. The slow replicative cycle characteristic of
HCMV requires the virus to maintain the host cell in a metabolically and translation-
ally active state for an extended period; thus HCMV is obliged to abrogate this type
of cellular response. A number of studies have shown that HCMV infection induces
several mechanisms to overcome the negative effects of stress responses and main-
tain translation (Child et al. 2004; Kudchodkar et al. 2004; Hakki and Geballe 2005;
Isler et al. 2005a, 2005b; Walsh et al. 2005; Hakki et al. 2006; Kudchodkar et al.
2006; Mohr 2006; Kudchodkar et al. 2007). In this chapter, we will concentrate on
the mechanisms by which cap-dependent translation is maintained during HCMV
infection by modulation of the phosphatidylinositol-3′ kinase (PI3K)-Akt-tuberous
sclerosis complex (TSC)-mammalian target of rapamycin (mTOR) signaling path-
way. The emerging picture is that HCMV-mediated regulation of this pathway is
multifaceted, thus ensuring that cap-dependent translation is maintained despite the
induction of a variety of cellular stress responses. Such dramatic alterations of this
pathway lead one to ask what other beneficial effects the virus might gain from these
changes and how these changes may contribute to HCMV pathogenesis.
Background: PI3K-Akt-TSC-mTOR Signaling
Akt (PKB) is the cellular homolog of the oncoprotein of the AKT8 retrovirus
(Bellacosa et al. 1991). Members of the mammalian Akt family, Akt1, 2 and 3, are
activated by PI3K in response to tropic factors (e.g., insulin and other mitogens);
other routes of activation are suspected (Datta et al. 1999; Plas and Thompson
2005; Sarbassov et al. 2005b). In Fig. 1, the binding of insulin to the insulin recep-
tor (IR) is used as an example of an Akt activator. IR activation results in tyrosine
phosphorylation of insulin receptor substrates (IRSs), this allows binding of the p85
regulatory subunit of PI3K to IRSs. Consequently, the PI3K catalytic subunit
(p110) is activated and phosphorylates phosphatidylinositol (PI)-4,5-bisphosphate
(PIP2) to PI-3,4,5-triphosphate (PIP3) on the plasma membrane. Both Akt and
phosphoinositide-dependent protein kinase-1 (PDK1) bind PIP3, allowing PDK1 to
be positioned to phosphorylate (activate) Akt on threonine 308 (T308).
Activated Akt affects multiple cellular targets that increase metabolism, growth
and proliferation while suppressing apoptosis (Summers et al. 1998; Ueki et al.
1998; Cass et al. 1999; Datta et al. 1999; Hill et al. 1999; Plas and Thompson
2005). All of these are beneficial to HCMV lytic growth. Thus, it is not surprising
that Akt is activated during HCMV infection (Johnson et al. 2001; Yu and Alwine
2002; Kudchodkar et al. 2006). One of the downstream effects of activated Akt is
the activation of mTOR kinase (also known as RAFT1 or FRAP) in mTOR com-
plex 1 (mTORC1, Fig. 1, described in detail in Sect. 3 below). Activation of
mTORC1 is critical for the maintenance of cap-dependent translation.
