Biology Reference
In-Depth Information
from RNA isolated from a healthy HCMV-seropositive individual, this transcript is
partially anti-sense to the viral UL81 and UL82 genes. Although a protein product
is expressed during productive infection, it has been suggested that LUNA could
function as an anti-sense RNA during latency, perhaps mediating the inhibition of
pp71 expression from the UL82 ORF. As pp71 is a potent transactivator of the
MIEP (major immediate-early promoter) (Bresnahan and Shenk 2000), such
suppression of the MIEP could help maintain latency.
Key Aspects of HCMV Latency and Reactivation
Although RNAs expressed in experimentally infected latent models do need to be
carefully interpreted, these model systems have also been used extensively to
attempt to address other key aspects of viral latency, namely latency establishment
and maintenance as well as reactivation.
The Establishment of HCMV Latency
One of the critical steps for establishing latency is likely to include the silencing
of the viral MIEP: such control of viral major IE gene expression is a credible
mechanism by which all subsequent viral lytic gene expression will be regulated
(Fig. 2). Thus, what regulates the MIEP? The MIEP appears to be regulated by
multiple cellular transcription factors and higher-order chromatin structure
during both lytic (Meier and Stinski 1996; Nevels et al. 2004; Ioudinkova et al.
2006; Reeves et al. 2006) and latent infection (Sinclair and Sissons 2006).
Promoter transfection assays have identified a number of factors that repress the
MIEP: including YY1 (ying yang 1) (Liu et al. 1994), ERF (ets-2 repressor
factor) (Bain et al. 2003) and Gfi-1 (growth factor independent-1) (Zweidler-
Mckay et al. 1996). These factors are expressed at high levels in nonpermissive
cells and, interestingly, ERF and YY1 are known to interact with chromatin-
modifying enzymes (Thomas and Seto 1999; Wright et al. 2005). Consistent with
this, during both experimental and natural latency, the transcriptionally inactive
MIEP is associated with markers of repressed chromatin, such as Heterochromatin
protein 1 (HP1), and is responsive to the histone deacetylase inhibitor Trichostatin
A (TSA) providing a model for silencing of the MIEP during experimental
(Meier 2001; Murphy et al. 2002; Reeves et al. 2005a) and natural latency
(Reeves et al. 2005b). Interestingly, during experimental latency in GM-Ps,
cellular factors associated with the formation of repressive chromatin (i.e. AML-1b)
are known to be upregulated (Slobedman et al. 2004). Therefore, such cellular
responses to latent infection, coupled with a cellular environment already high in
levels of repressors of the MIEP, may be critical determinants for the establishment
and maintenance of latent carriage of viral genomes.
