Biology Reference
In-Depth Information
Without claiming to be right, in this review we would like to reserve the term
latency for the maintenance of the viral genome in the absence of productive
infection, that is, without assemblage of infectious virions. In contrast, the term
persistence is used to describe a situation of enduring or at least long-lasting
virus production, which may occur at a low level. In the past there was a debate
whether low-level productive infection can ever be excluded to meet the strict
definition of latency. Improved assays for detecting infectious virus combined
with highly-sensitive RT-PCRs specific for transcripts of essential genes, such as
M122
(
ie3
) and
M55
(
gB
), have provided reasonable evidence allowing the
conclusion that the viral genome can indeed be maintained without completion
of the productive cycle (Kurz et al. 1997; 1999; Pollock and Virgin 1995).
In accordance with this, conditionally replication-incompetent, temperature-
sensitive mutants of mCMV were shown to establish and maintain latency, and
to reactivate gene expression up to the mutation, at which point the reactivation
stopped (Bevan et al. 1996).
Whereas most host organs can be sites of mCMV latency, mCMV persistence
occurs at a privileged site, namely the tissue of the salivary glands and, therein,
specifically the glandular epithelial cell, which is a polarized cell type specializ-
ing in secretion. Virion morphogenesis in this cell type is special in that huge
numbers of monocapsid virions gather in secretory vacuoles and are released into
the salivary duct, which is an important route for virus host-to-host transmission
via saliva. Persistence in glandular epithelial cells occurs despite a vigorous
immune response in salivary gland tissue (Cavanaugh et al. 2003), although it
eventually ceases, unless the host is depleted of CD4 T cells (Jonjic et al. 1989),
indicating that CD4 T cells function as antiviral effector cells and clear salivary
gland infection in the long run. Recent work by Humphreys and colleagues (2007)
has suggested that mCMV exploits the privileged mucosal environment, which
favors the development of interleukin (IL)-10-expressing CD4 T cells and disfa-
vors the development of antiviral interferon (IFN)-γ-expressing effector CD4 T
cells. In fact, these authors demonstrated that systemic blockade of IL-10-receptor
signaling leads to accumulation of IFN-γ-expressing CD4 T cells in the salivary
glands associated with control of salivary gland infection, though it remained
open to question whether the virus failed to disseminate to the salivary glands or
was controlled there locally.
Viral functions, however, appear to be actively involved, since several viral
genes have been implicated in persistent infection of the salivary glands.
M33
,
M43
, and
sgg1
mutants, competent for replication in cell culture as well as in
various organs, showed a defect specifically in salivary gland replication (Davis-
Poynter et al. 1997; Lagenaur et al. 1994; Xiao et al. 2000). Interestingly, such a
specific effect on salivary gland tropism, and thus on mCMV persistence, was
also recently attributed to a noncoding 7.2-kb RNA ortholog of the hCMV 5-kb
RNA, which is a stable intron (Kulesza and Shenk 2006).
Persistence in the salivary glands can occur, logically, only when the virus
disseminates to the salivary glands and infects the glandular epithelial cells.
As a consequence, deletion of or mutations in viral genes involved in replicative
