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Viral Gene Expression Associated with HCMV Latency
Using an experimental latent model system involving in vitro infection of GM-Ps,
Kondo et al. first identified cytomegalovirus latency-expressed transcripts (CLTs)
from both strands of the MIE region of the genome (Kondo and Mocarski 1995;
Kondo et al. 1996). Subsequently, some of the CLTs were identified in the cells of
healthy seropositives' bone marrow aspirates and antibodies to these six ORFs were
detected in infected individuals (Kondo et al. 1996; Landini et al. 2000). However,
their specific role, if any, in latency is unclear as they are expressed during produc-
tive infection and deletion of one CLT (pORF94) had no impact on the ability of
the virus to establish latency or to reactivate in vitro (White et al. 2000).
Using the same experimentally latent GM-P model, another putative latency-
associated transcript has been identified (Jenkins et al. 2004): the UL111a transcript,
also expressed during lytic infection (Kotenko et al. 2000). UL111a encodes a viral
homologue of interleukin-10 (vIL-10). Unlike its cellular counterpart, vIL-10
encodes only the immunosuppressive functions associated with cellular IL-10
(Spencer et al. 2002) and thus may play a role in avoiding immune surveillance (see
the chapter by C. Powers et al., this volume). This provides an attractive mechanism
for the increased survival of latently infected cells in vivo. However, detection of
the transcript in vivo did not correlate with HCMV serostatus: monocytes from
some seronegative individuals were also positive for the v-IL10 transcript. Whether
such seronegative donors were DNA-positive or were, perhaps, sero-converting at
the time of the analysis was never determined.
More comprehensive analyses of viral gene expression associated with experi-
mental latency have also been carried out using microarrays (Goodrum et al. 2002;
Cheung et al. 2006). These detected a large number of viral RNAs, including IE
transcripts that were expressed transiently following infection of CD34 + cells or
GM-Ps. Consequently, whether all these viral RNAs represent truly latent transcripts
requires more in depth analysis. The possibility that some of these viral RNAs may
reflect detection of low-level persistent infection in some cells of the experimental
latent cultures needs to be completely ruled out. Although the possibility that
expression of these virals RNAs are required to establish latent infection, which are
progressively switched off during long-term latency, needs consideration (Cheung
et al. 2006).
One transcript, however, initially identified by Goodrum et al. with their microarray
analysis (Goodrum et al. 2002), has also been shown to be expressed during natural
latency in some seropositive monocytes and CD34 + cells (Goodrum et al. 2007).
This transcript, encoded by UL138 of the viral genome, may be required for HCMV
latency as recombinant viruses lacking UL138 have an impaired ability to establish
a latent infection in an experimental model system (Goodrum et al. 2007). However,
the exact role of this transcript during latency will require further investigation.
Another recently identified putative latency-associated transcript encoded by
HCMV is the LUNA (also known as latency-associated nuclear antigen) transcript
(Bego et al. 2005). Identified in a screen of a monocyte cDNA library prepared
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