Biology Reference
In-Depth Information
signaling pathways (Fortunato et al. 2000; Simmen et al. 2001; Johnson and Hegde
2002; see the chapters by A. Yurochko and M.K. Isaacson et al., this volume). Viral
tegument proteins are also delivered to the cell which can target cellular functions
(Everett 2006; see the chapter by G. Maul, this volume). Finally, some of these viral
tegument proteins delivered by the virion particle are known to transactivate gene
expression to promote high levels of viral IE transcription (Liu and Stinski 1992;
Bresnahan and Shenk 2000; Schierling et al. 2004; see the chapter by R; Kaletja,
this volume). However, none of these are likely to be involved in reactivation from
latency as no virions will be present in the apparent absence of these events during
latency; the switch from a latent to a reactivating phenotype requires a latency
breaking step. Whether this is a virally encoded latent function or is a consequence
of changes to the cellular environment is presently under intense investigation in a
number of laboratories.
In our laboratory, we have shown that reactivation of viral gene expression and
productive infection in natural (Reeves et al. 2005b) or experimental latency
(Murphy et al. 2002; Reeves et al. 2005a) is associated with differentiation of
CD34
+
cells to a DC phenotype. Histone acetylation at the MIEP facilitates an open
chromatin conformation which is permissive for MIEP transcription (Reeves et al.
2005b). Consequently, the implication is that normal changes in cellular transcrip-
tional regulators which occur upon terminal differentiation of myeloid cells could
be enough to trigger reactivation of virus IE gene expression.
The likelihood that reactivation from latency occurs in the absence of virally
encoded transactivators of IE gene expression implies that the viral genome senses
reactivation signals from cellular mediators. The first report of reactivation in vitro
from myeloid cells involved the stimulation of monocytes with cytokines derived
from allogeneically stimulated T cells (Soderberg-Naucler et al. 1997), including
TNF-alpha, interferon-gamma, interleukins and GM-CSF (Soderberg-Naucler et al.
2001). Pro-inflammatory factors or induction of myeloid cell differentiation have
been responsible for promoting reactivation of viral major IE gene expression. This
scenario may have strong clinical relevance, considering the known association of
virus reactivation and CMV disease with transplantation (Sissons et al. 2002).
Attempts to further characterise the role of the cytokines have, so far, proved
inconclusive and await further study.
Besides the basic regulation of viral IE expression, it is also clear that the interplay
between the host immune system and reactivating virus has a profound role in
HCMV reactivation in vivo (Sissons et al. 2002; Peggs and Mackinnon 2004).
Possibly, HCMV reactivation is a sporadic event, occurring infrequently when
certain inflammatory conditions are encountered locally in the host. Alternatively,
it could be a more common event, occurring whenever latently infected myeloid
cells naturally differentiate. In both cases, any reactivation and virus dissemination,
which could result in severe disease, is efficiently controlled by a robust immune
response. This may be the reason for the unprecedented number of memory T cells
that recognise lytic HCMV antigens from healthy carriers in vivo (Riddell et al.
1991; McLaughlin-Taylor et al. 1994; Wills et al. 1996; Sylwester et al. 2005). Both
scenarios are possible and it is likely that that the exact mechanism could lay some-
