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mRNAs are fairly stable with half-lives of more than 24 h and of approximately 6
h determined for IE1 and IE2, respectively (Simon et al. 2007). Thus, absence of
MIE locus transcripts, of IE1 mRNA in particular, is a good negative marker for
latency. We have recently proposed to use the term MIE locus latency to characterize
the state of viral genomes that are silenced at this essential regulatory gene locus
(Simon et al. 2006b).
Latent Viral Genome Load Defining the Risk of Recurrence
Epidemiologically, CMV infections can occur at any age, but frequently, CMVs
are acquired by their respective hosts perinatally or during early childhood.
Regardless of the time of virus acquisition, latency is eventually established.
A CMV-specific immune status, i.e., the presence of CMV-specific memory CD4
and CD8 T cells as well as of antibodies, testifies for a resolved acute infection
in the past, which may have been years or decades ago. Importantly, clinicians
use CMV-antibody status to define donor-recipient risk constellations for CMV
recurrence and disease in solid organ and hematopoietic stem cell transplanta-
tions. The individual infection history of donor and recipient, however, is usually
unknown. Although it is clear that presence of latent CMV in either the donor or
the recipient, or in both, indicates a risk in a qualitative sense, the incidence of
CMV reactivation is difficult to predict.
The mouse model has revealed that infection history matters (Reddehase et al.
1994). Mice infected as neonates within 24 h after birth showed delayed clear-
ance of acute, productive infection in organs and prolonged persistence in the
salivary glands, whereas fully immunocompetent mice infected as adults rapidly
controlled acute infection in all organs and showed a shortened persistence in the
salivary glands. Months later, during replicative latency, this different history of
primary infection was reflected by high or low load of viral genomes, respec-
tively, in organs including lungs, spleen, heart, kidney, adrenal glands, and
salivary glands. Importantly, viral DNA load is a predictor of the risk of virus
recurrence after hematoablative total-body γ-irradiation, with high or low load
predicting high or low incidence of recurrence, respectively. Recurrence turned
out to be a focal and stochastic event occurring independently in different latently
infected organs, thus leading to all possible combinations of virus detection in
single or multiple organs. These findings indicate that recurrence is a generally
rare event emerging from a minority of the latent viral genomes, and they provide
an immediate explanation for the causal relationship between the number of
latent virus genomes in tissues and the probability of reactivation. In accordance
with such a causal relationship, limitation of acute infection by CD8 T cells in a
mouse model of adoptive immunotherapy of CMV infection resulted in a dose-
dependent reduction of both latent viral genome load and incidence of virus
recurrence (Steffens et al. 1998).
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