Murine Model of Cytomegalovirus Latency and Reactivation - Human Cytomegalovirus - page 308

us with riddles is m128 , also known as mCMV ie2 , which is part of a bidirectional
gene pair constituting the major immediate early (MIE) locus (see Sect. 4), a
regulatory locus thought to be of key importance for kick-starting viral gene
expression in acute infection and reactivation from latency; nevertheless, no in
vivo function could so far be attributed to m128 ( ie2 ) in acute infection or latency
(Cardin 1995). As latency and reactivation are events in virus biology that are
closely linked to host cell functions such as cell cycle, gene silencing, and nucle-
otide metabolism, one may propose that currently unknown functions of at least
some of the viral private genes will be involved in the establishment, maintenance,
and breaking of latency.
By definition, due to the lack of homology, the function of mCMV private
genes gives no direct prediction for the function of hCMV private genes. Although
this might be considered a weakness of the murine model, there is good reason to
anticipate that principles of virus-host interactions in latency and reactivation are
analogous between different virus-host pairs. This hope is justified from the
previous experience with mCMV private genes m152 and m06 , which interfere
with the MHC class I pathway of antigen presentation. Specifically, m152/gp40
was the first CMV immunoevasin to be described and has greatly stimulated the
search for a similar function in hCMV. As in the co-evolution between mCMV
and its host species mouse, co-evolution of hCMV and the human species has
indeed led to gene functions interfering with the MHC class I pathway of antigen
presentation, namely US2/US11 , US3 , and US6 (for a review, see Reddehase
2002). This example indicates that analogous selective forces, in this case exerted
by the respective hosts' immune systems, can lead to convergent results, albeit the
solutions may differ in the molecular details. The value of the murine model is
that the consequences of mutations in private genes—consequences that we
expect to occur only upon interaction with host functions in the context of host
tissues and organs—can be tested systematically in vivo.
Complete gene silencing in a viral episome with closed higher-order chromatin-
like structure, that is, immune evasion by hiding , appears to be a reasonable
mechanism for maintenance of the viral genome in the face of fully developed
host immunity. Although this is probably true for the vast majority of latent viral
genomes in host tissues at any particular time point, recent data have indicated
that latency is not static, but is highly dynamic, involving a permanent immune
surveillance by CD8 T cell-mediated sensing of early stages of transcriptional
reactivation.
Definitions and Caveats: The Difference Between Latency
and Persistence
There is some semantic confusion in the field regarding the terms latency and
persistence , which are sometimes used as synonyms to describe the situation that
an infection is not cleared but persists in the host for an extended period of time.