Biology Reference
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signaling was also reduced following cholesterol depletion. To confirm a link
between entry and IFN activation, we used several novel inhibitors of HCMV entry
including a small protein fragment encompassing the disintegrin-like domain of gB
and a beta amino acid oligomer that mimics the heptad repeat region of gB (A.L.
Feire and T. Compton, unpublished results; English et al. 2006). HCMV-induced
interferon signaling was diminished in the presence of these inhibitors, providing
further evidence that the IFN activation pathway is connected to downstream events
in the entry pathway (L. K. Juckem and T. Compton, unpublished results).
The rapid and direct induction of innate immune responses by HCMV suggests
that they are triggered during virus binding and entry into cells. The ability of the
virus to activate innate immune signaling in the absence of virus replication and
de novo protein synthesis further emphasizes the importance of structural compo-
nents of the virus. Understanding the coordination of innate immune activation
with virus entry is a daunting task due in part to the high level of complexity
associated with the molecular events of HCMV entry. Multiple copies of envelope
glycoproteins decorate HCMV virions and interact with several cellular receptors
to mediate entry into cells (Wang et al. 2003, 2005; Feire et al. 2004). The known
interaction between receptors and viral glycoproteins is summarized in Table 2.
The importance of gB and gH is exemplified by their roles in entry and both
branches of innate immune activation. To date we have found no role for TLR2/1
heterodimer as an entry receptor (K.W. Boehme and T. Compton, unpublished
results). Our recent work comparing the requirements for HCMV-induced IC and
IFN activation revealed differential regulation. We were able to explore the early
events in the HCMV entry process and determine an order to the innate immune
activation. The IC response is initiated first by outright sensing of the virus
through TLR2 and occurs even if tegument delivery of pp65 is blocked. This
activation may be coincident with transfer of HCMV from an initial tethering to a
more stable docking step with other cellular receptors. The HCMV-induced IFN
response occurs by a postbinding or fusion-dependent mechanism that is dependent
on the organization of cholesterol-rich microdomains and is diminished in the
presence of HCMV entry inhibitors (L.K. Juckem and T. Compton, unpublished
results). Much more work remains to be done to elucidate the underlying
mechanism of HCMV-mediated IFN signaling, which may be triggered through:
(a) stable binding to cellular receptors, (b) the physical fusion event, and (c)
delivery of virion contents into the cytoplasm.
Table 2
Interaction between receptors and viral glycoproteins
Pathway
Cellular component
Virus component
Coordination
IC activation
TLR2/1
gB
Outright sensing prior to entry
gH
CK2 (packaged)
IFN activation
Unknown
gB
Linked to entry pathway
gH
Fusion event?
