Biology Reference
In-Depth Information
pUL47, pUL48 and pUL69 should also be examined during viral entry in both the
presence and absence of MT inhibitors to determine which tegument-delivered
proteins remain associated with the capsid and thus travel along MTs during viral
entry. In addition, a closer examination of the UL26-null virus that appears to
have a general defect in tegument formation or stability (Lorz et al. 2006; Munger
et al. 2006) could be informative. Is dynein required for the cytoplasmic transport
of HCMV capsids toward the nucleus as it is for HSV-1 (Dohner et al. 2002)? If
so, to which tegument protein does it bind? Also, how is the viral DNA released
from the capsid, through the nuclear pore and into the nucleus? Empty HCMV
capsids docked at the nuclear pore complex that presumably had already released
their DNA into the nucleus have been observed by TEM (Ogawa-Goto et al.
2003). For HSV-1, the pUL36 protein that is required for DNA release also binds
to viral DNA (Chou and Roizman 1989), but it is not clear if this binding plays a
role during the release of the genome into the nucleus. Cellular proteins may also
play a role in this process, as they do for other viruses (Greber and Fassati 2003).
Finally, does one or more of the many cellular signaling pathways induced upon
HCMV infection (see the chapter by A. Yurochko, this volume) help during the
transport of capsids to the nucleus? Kaposi's sarcoma associated herpesvirus
(KSHV) and adenovirus also induce host cell-signaling pathways upon infection,
and the activation of these pathways facilitates the MT-directed transport of viral
capsids to the nucleus (Naranatt et al. 2005; Suomalainen et al. 2001). Most of the
work on the very early stages of HCMV infection has focused on prefusion mem-
brane events or mechanisms of IE gene expression. Although those are defining
events in the viral life cycle and certainly merit intense investigation, the time
period in between them represents an important, understudied stage of HCMV
infection.
Initiating Viral IE Gene Expression
Once viral genomes enter the nucleus, a subset of them associate with subnuclear
structures (Ishov et al. 1997) called PML nuclear bodies (PML-NBs), which are
sometimes called PODs for PML oncogenic domains or ND10 for nuclear domain
10 (see the chapter by G. Maul, this volume). PML-NBs are visualized as numerous
dot-like structures in nuclei, and are built around the PML (promyelocytic leuke-
mia) protein. Other prominent PML-NB proteins include Sp100 and Daxx (Everett
and Chelbi-Alix 2007). In the absence of PML, other PML-NB proteins do not
co-localize with each other, but are dispersed throughout the nucleus, indicating
that the PML protein is required for the integrity of PML-NBs (Ishov et al. 1999).
The role of these structures in HCMV-infected cells is beginning to emerge.
Only the HCMV genomes located next to PML-NBs appear to be transcribed,
leading to the hypothesis that PML-NBs represent a preferred site for viral gene
expression (Ishov et al 1997). However, the proteins that localize to PML-NBs act
as transcriptional repressors (Everett and Chelbi-Alix 2007), and many viruses,
including HCMV, disrupt PML-NB structures at very early times after infection
