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et al. 1998), and presumably without lytic DNA replication, this region of the viral
genome may act as a latent origin of replication or encode a viral gene product
essential for maintenance of the viral genome. Characterisation of this region
awaits further study.
If latent replication of HCMV genomes does occur, how is segregation of viral
genomes to the daughter cells accomplished? This is achieved in EBV and KSHV
by using chromatin tethering proteins such as EBNA-1 (Leight and Sugden 2000)
and LANA (Cotter and Robertson 1999), respectively. In the absence of an identified
homologue in HCMV, how the viral genomes are replicated and segregated during
latent carriage is not known.
One alternative, which needs to be considered, is that there is actually no latent
replication of HCMV DNA. Instead, CD34
+
haematopoietic cells exiting the bone
marrow are continually infected from a low level subclinical persistent infection in,
for instance, surrounding stromal cells. Once these CD34
+
cells enter the blood-
stream, they are relatively short-lived and quite quickly differentiate, which results
in virus reactivation and virus production from these terminally differentiated
myeloid cells. Whether or not any of these models are true will require further
study, in perhaps more tractable model systems than we have at present.
The maintenance of HCMV latency is likely to require the continued repression
of viral gene expression - particularly IE gene expression - to prevent the virus from
re-entering the lytic cycle. In experimentally latent cells, the MIEP is associated
with repressed chromatin upon infection (Murphy et al. 2002) and throughout
long-term culture as CD34
+
cells (Reeves et al. 2005a). Similarly, in naturally latent
cells from healthy individuals the MIEP is associated with repressed chromatin
(Reeves et al. 2005b). This suggests that virus is kept latent, at least in part, by the
recruitment of repressive chromatin factors to the MIEP. However, chromatin is a
highly dynamic structure and thus it may be a possibility that yet undefined viral
functions have a role in the maintenance of the MIEP in a repressed form, which
may also impact on the carriage of the viral genome in a latent state.
Reactivation of HCMV from Latency
Latency is operationally defined as the persistence of the viral genome in the
absence of viral lytic gene expression, but importantly, with the capacity of the
virus to re-enter its lytic life cycle. The ease and rapidity with which HCMV
reactivates in vivo, causing severe disease, is in stark contrast to the ability to reactivate
in vitro.
Observations from both experimentally and naturally latent cells suggest that the
cellular environment is a key factor in HCMV reactivation: changes in the cellular
environment result in the induction of viral lytic gene expression and, hence, virus
reactivation (Fig. 3). A number of functions associated with virus infection are
known to augment viral IE gene expression. Virus binding on the surface of the cell
results in significant changes to the cellular environment by targeting a number of
