Biology Reference
In-Depth Information
for virus recurrence requires desilencing of all essential genes, at least temporarily.
In theory, an essential locus does not need to remain open all the time, as transcripts
and proteins are often quite stable. For instance, IE1 and IE2 mRNAs were found
to have half-lives of more than 24 h and of 6 (5-7) h, respectively (Simon et al.
2007), so that a single window of open chromatin conformation at the MIE locus
could possibly provide MIE mRNA sufficient for the whole productive cycle of
approximately 24 h. Hummel et al. (2007) have used the spleen explant model
of mCMV reactivation to show that inhibition of DNA methylation and inhibition
of the histone deacetylase, the latter of which favors hyperacetylated loose
chromatin, act synergistically in inducing
ie1
gene expression as well as virus recur-
rence. These findings support the conclusion that gene silencing and chromatin
structure, as in hCMV, are also involved in the regulation of mCMV latency.
Notably, at least under the conditions of tissue explant cultures, TNF-α signaling did
not appear to play a crucial role (Hummel et al. 2007).
Dynamic Control of Latency at Immunological Checkpoints:
The Immune Sensing Hypothesis
Besides epigenetic control of latency, it is likely that the host immune system will
take note of antigens presented on the cell surface of latently infected cells following
reactivated gene expression. An immune response may terminate reactivation at
various steps prior to virion morphogenesis and release. Thus, although the immune
system may not recognize latently infected cells in a state of complete transcrip-
tional latency, it contributes to the maintenance of replicative latency by stopping the
reactivation. An involvement of the host immune system in latency control was
indicated early on by the clinically relevant hCMV reactivation and recurrence in the
immunocompromised patient. Proof of concept was provided in the mouse model
by mCMV recurrence after depletion of lymphocyte subsets involved in innate and
adaptive immunity, with a hierarchy pointing to a pivotal role for CD8 T cells (Polic
et al. 1998). Likewise, global ablation of cellular immunity by total-body γ-irradia-
tion was found to facilitate virus recurrence in vivo (Balthesen et al. 1993; Kurz and
Reddehase 1999; Kurz et al. 1997; Reddehase et al. 1994; Steffens et al. 1998).
Astoundingly, although virus recurrence became detectable in literally all lungs
of latently infected mice after total-body γ-irradiation, detailed and quantitative
statistical analysis of the patterns of transcriptional reactivation and virus recur-
rence revealed that by far most of the viral genomes still remained in a state of MIE
locus latency, indicating that epigenetic control dominates over immune control.
Loss of immune control, however, led to an increased number of progressing
transcriptional reactivations with prevalences of IE1 transcripts > IE1 plus IE3
transcripts > IE1 plus IE3 plus M55 (gB) transcripts, but only a few transcriptional
reactivations culminated in the recurrence of infectious virus (Kurz and Reddehase
1999). Thus, even in the absence of cellular immune control, recurrence is a rare
end point of transcriptional reactivation.
