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In-Depth Information
Figure 1 illustrates that signals initiated on receptor binding may prime the cell
for subsequent events during viral entry (1). Mediated by tightly associated tegu-
ment proteins such as pUL47, pUL48 and perhaps pp150, capsids are transported
along microtubules (MTs) toward the nucleus (2). Cellular motor proteins such as
dynein likely assist this transport. Other tegument proteins not directly associated
with capsids (such as pp65 and pp71) are transported independently to the nucleus
(3). Through unknown mechanisms, capsids dissociate from MTs, dock at nuclear
pores, and release their DNA into the nucleus (4). Viral genomes associate with cel-
lular histones (H; 5) and are packaged into chromatin. The Daxx protein, which rap-
idly dissociates from and reassociates with PML-NBs (6) interacts, in an
uncharacterized way, with the viral genome (7), presumably at the major immediate
early promoter (MIEP) and perhaps other IE promoters as well. Daxx recruits an
HDAC and silences viral gene expression (8) by establishing a repressive chromatin
structure. Other PML-NB components are also recruited and participate in the
silencing of viral gene expression (8). pp71 binds to Daxx in the newly formed
PML-NBs that are silencing infecting viral genomes (9) and induces Daxx degrada-
tion (10), thus de-repressing viral IE gene expression (11). The viral IE1 gene prod-
uct subsequently dismantles PML-NBs and neutralizes the repressive effects of one
or more of the proteins that localize to these structures (not shown).
Perspectives
Future work should focus on identifying how, where and when during entry the
tegument disassembles, the process of histone association with viral genomes, how
Daxx and other PML-NB proteins are recruited to viral genomes, how other tegu-
ment proteins cooperate with pp71 (and then IE1) to inactivate the cellular defenses
mediated by the PML-NB proteins and how signal transduction cascades induced
upon viral entry impact on each of these processes.
Additionally, the question as to whether PML-NBs are either pro-virus or
anti-virus needs to be answered. Interestingly, recent evidence suggests that the
real answer may be that PML-NBs have both negative and positive effects on
the HCMV life cycle. While these proteins clearly inhibit lytic replication (and
thus are anti-virus), recent evidence suggests that Daxx may be absolutely nec-
essary to silence expression from the viral genome when latency is established
and thus avoid an abortive infection in undifferentiated cells where productive
lytic replication cannot be completed (Saffert and Kalejta 2007). Thus, for
latent HCMV infections, Daxx could be considered to be pro-virus as well.
More work is needed to explore the possibility that HCMV uses the same cellu-
lar defense to establish latency that it easily and systematically inactivates at the
start of lytic infections.
Acknowledgements
My thanks are extended to Leanne Olds for the illustration in Fig. 1, and to
my students Ryan Saffert, Adam Hume, and Jiwon Hwang for stimulating discussions and com-
ments on the manuscript. Work in my lab is supported by the American Heart Association
