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et al. 2004). Similarly, HCMV activates TLR2 through a physical interaction with
gB and gH, to mediate the cellular IC response (Compton et al. 2003; Boehme et al.
2006). TLR2 functional blocking antibodies diminish HCMV-induced IC signaling
and a soluble version of gB (gBs) has an inherent ability to induce IL-6 and IL-8
secretion in a TLR2-specific manner (Boehme et al. 2006). Recently we found that
the HCMV-mediated IC response is independent of the organization of cholesterol-
rich microdomains within the plasma membrane and is not blocked by postbinding
HCMV entry inhibitors (L. Juckem and T. Compton, unpublished results). This sug-
gests that the IC response is initiated through TLR2 by outright sensing of the virus
during the earliest events in the entry process. The ability of viral glycoproteins to
serve as PAMPs is somewhat surprising since the virus-encoded proteins are synthe-
sized by host machinery and ultimately bear protein modifications that are reflective
of the host. However, all known viral envelope proteins that are recognized by TLRs
share a mutual role in virus entry, suggesting that they may possess unique structural
conformations that are recognized by the TLRs.
Recently a parallel mechanism of HCMV-induced NF
κ-B activation in response
to HCMV has been proposed. It was found that HCMV packages the cellular
kinase, casein kinase 2 (CK2), within its tegument during assembly and egress
(Varnum et al. 2004). It has been hypothesized that virus-cell fusion deposits the
additional constitutively active CK2 molecules into the cytoplasm where they can
directly phosphorylate inhibitory IκBα proteins, thereby activating NF
κ-B (Nogalski
et al. 2007). The contribution of CK2 to the HCMV-induced IC response remains
to be fully elucidated.
Activation of Interferon Responses
The type I interferon response, consisting of interferon β and multiple forms of
interferon α, is produced in response to viral infection and restricts replication at
the earliest stages (reviewed in Stark et al. 1998). Interferon activation is accompa-
nied by the induction of interferon-stimulated genes (ISGs), a subset of cellular
genes that carry out many of the antiviral functions of interferon (reviewed in
Theofilopoulos et al. 2005). The type I interferon response to virus infection can be
divided into two phases: the activation phase and the amplification phase. Virus
infection, but not interferon treatment, activates the initial activation phase through
the key regulatory transcription factor, IRF3. Signal transduction pathways, which
remain incompletely characterized, lead to virus-induced phosphorylation of IRF3
on the carboxyl terminal serine residues by the related kinases TBK1 and IKKε
(Servant et al. 2001; Fitzgerald et al. 2003; Sharma et al. 2003). This results in the
homodimerization and translocation of IRF3 to the nucleus where it can interact
with the co-activators, CREB binding protein (CBP) and p300, and form a complex
that drives the transcription of interferon β and a subset of ISGs (reviewed in
Taniguchi and Takaoka 2002). The nascent interferon is then able to act in an auto-
crine and paracrine manner to initiate signaling through the cellular α/β interferon
