Murine Model of Cytomegalovirus Latency and Reactivation - Human Cytomegalovirus - page 319

Concluding Thoughts and Perspectives
Although transition to IE3 was observed with the mutant virus, reactivation did
not proceed to M55 (gB) transcripts and virus recurrence. It is proposed that
immunological checkpoints in series, defined by presentation of antigenic pep-
tides, exist downstream of IE1. Expansion in latently infected lungs of CD8-T EM
specific for the D d -presented peptide 257-AGPPRYSRI-265 (Holtappels et al.
2002; Simon et al. 2006a), which is derived from the E-phase protein m164/
gp36.5, predicts a second immunological checkpoint, and further checkpoints may
wait in line in case the first two checkpoints fail due to mutations in virus variants.
Simultaneous expansion of IE1-specific and m164-specific CD8-T EM during
latency of wild type mCMV (Holtappels et al. 2002) predicted a leakiness of the
IE1 checkpoint; nevertheless, we were so far unable to detect m164 mRNA during
latency. This paradox might be explained by effective elimination of cells present-
ing the m164 epitope, which limits the chance for detection. A mutant virus with
engineered deletion of both the IE1 and the m164 epitope, i.e., the recombinant
virus mCMV-IE1-L176A+m164-I265A, should confirm the proposed second
immunological checkpoint and might reveal the existence of a third one.
Experiments in progress have shown that CD8 T cells specific for a newly defined
epitope in ORF m145 are expanded in the memory pool after ablation of epitopes
IE1 and m164 (Holtappels et al., unpublished data), and viral transcription during
pulmonary latency of this mutant is currently under investigation.
It is important to note that number and type of viral ORFs determining immu-
nological checkpoints are not fixed but vary between individuals in reflection of
MHC polymorphism in the population, depending upon the usually diploid set of
peptide-presenting MHC class I molecules specified by the individual host's
genome as well as on the proteome(s) of the latent virus variant(s) specifying the
repertoire of potentially antigenic peptides. Thus, the model proposes a private
pattern of immunological checkpoints for each latently infected individual.
A putative role for viral immunoevasins in canceling immunological check-
points and facilitating virus recurrence is an intriguing aspect for future research in
this field.
Acknowledgements The authors are supported by the Deutsche Forschungsgemeinschaft,
Sonderforschungsbereich 490, individual project E2 “Immunological control of latent cytomega-
lovirus infection”.
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