Biology Reference
In-Depth Information
general, and experimental tissue explantation, which apparently all trigger mCMV
transcriptional reactivation and recurrence (Hummel and Abecassis 2002; Jordan
1983; Reddehase et al. 2002). All these conditions are multifactorial and many
involve a cytokine storm and deprivation of immune control. Attempts to dissect
these multifactorial conditions on a molecular level have recently focused on tumor
necrosis factor (TNF)-α, which is known to signal to CMV MIE enhancers through
transcription factors NF-κB and AP-1 (Hummel et al. 2001; Prösch et al. 1995) (for
enhancer mechanics, see the review by Meier and Stinski 2006).
Although the canonical NF-κB-dependent pathway of MIE enhancer activation
appears to be dispensable for virus replication in cultured fibroblasts (Benedict
et al. 2004), TNF-α signaling clearly enhanced the prevalence of mCMV MIE gene
expression as well as the amount of MIE transcripts per transcriptional event in
latently infected lungs within 24 h after intravenous administration of the cytokine
(Simon et al. 2005). Notably, this signaling also helped to overcome the splicing
checkpoint, which resulted in the expression of the transactivator IE3 mRNA, but
transcriptional reactivation did not proceed to expression of the essential gene
Μ55
(
gB
), thus predicting the existence of further checkpoints beyond MIE locus gene
expression. As a consequence, although TNF-α may play an important role in
enhancing the initiation of virus reactivation, additional conditions must be met for
completion of the productive cycle. Notably, intraperitoneal administration of
TNF-α or IL-1β triggered mCMV recurrence in latently infected lungs with a delay
of 3 weeks (Cook et al. 2006). Likewise, as a correlate for the sepsis model of
mCMV reactivation (Cook et al. 2002), lipopolysaccharide was found to reactivate
latent mCMV through a TLR-4-dependent pathway (Cook et al. 2006).
These findings are not in conflict with the direct effects of TNF-α on the MIE
enhancer but may rather indicate that TNF-α as well as other proinflammatory
mediators can trigger a cascade of events that eventually provide all the conditions
for virus recurrence. As mCMV recurrence in the study by Cook et al. (2006) was
achieved with near-lethal doses of TNF-α, the question arises of whether the
cytokine's effects on the endothelia, causing microvascular injury, may be involved
in a pathogenetic process facilitating virus reactivation.
Role of Viral Chromatin Remodeling
There exists reasonable evidence to suggest that the latent hCMV genome is main-
tained as an episome associated with cellular histones in a nucleosome-like but not
nucleosome-identical higher-order chromatin-like structure, and remodeling of
viral chromatin is considered to have a critical role in regulating MIE locus activity
(for a review see Bain et al. 2006; see the chapter by M. Reeves and J. Sinclair, this
volume). Although little is known about the physical state of the latent mCMV
genome, analogy suggests that it also exists as an episome associated with cellular
histones. Obviously, MIE locus desilencing by local opening of the viral chromatin
is a prerequisite for MIE gene transcription, and completion of the productive cycle
