Biology Reference
In-Depth Information
The observation of recurrence after lymphocyte subset depletion or after
γ-irradiation is not a formal proof for an immune control of latency, since in vivo
cell depletion is associated with a cytokine storm, and since γ-irradiation represents
genotoxic stress inducing DNA repair, which both could trigger virus recurrence by
pathways unrelated to the ablation of cellular immune control.
That immune sensing of early stages of virus reactivation, specifically the
recognition of MHC class I-presented antigenic peptides by CD8 T cells, may
indeed be involved in the control of latency was first suggested in the BALB/c
mouse model of pulmonary latency by the finding that activated, CD62L
low
effector-memory CD8 T cells (CD8-T
EM
) specific for the immunodominant L
d
-
presented IE1 protein-derived peptide 168-YPHFMPTNL-176 expand in latently
infected lungs and accumulate there over time (Holtappels et al. 2000). This
immunological finding in combination with the molecular finding of MIE locus
gene expression during pulmonary latency (Kurz et al. 1999; Grzimek et al.
2001) led to the idea that presentation of the IE1 peptide in cells with desilenced
MIE locus iteratively restimulates IE1 epitope-specific CD8-T
EM
, which then
terminate the reactivation event by virtue of their effector functions. This is
called the
immune sensing hypothesis of latency control
(Fig. 2 ) (Holtappels
et al. 2000; Simon et al. 2006a, 2006b).
Evidence in support of this hypothesis was provided recently with recombinant
virus mCMV-IE1-L176A, in which antigenicity and immunogenicity of the IE1
peptide are specifically wiped out by the amino acid point mutation Leu replaced
with Ala at the C-terminal MHC class I anchor residue. When compared with the
corresponding revertant virus mCMV-IE1-A176L, the mutant virus showed a pro-
nounced transcriptional phenotype in latently infected lungs in that the prevalence
of IE1 transcripts was fivefold increased in accordance with the lack of IE1 epitope-
specific antiviral effector cells (Simon et al. 2006a). This clearly implies that the
true incidence of MIE locus desilencing is underestimated in lungs latently infected
with wild type or epitope-rescued mCMVs due to the termination of a large fraction
of MIE locus reactivation events by the IE1 epitope-specific CD8-T
EM
.
Fig. 2
(continued) which terminate the transcription and expand clonally. This defines the first
immunological checkpoint.
b
Viral gene transcription and immune sensing during latency of mutant
virus mCMV-IE1-L176A. Replacing Leu with Ala at the C-terminal MHC anchor position of the IE
peptide eliminates IE1 antigenicity and thereby inactivates this checkpoint. Transcription/splicing
proceeds to IE3 (which does not contain a CD8 T cell epitope for
H-2
d
) and to the E-phase transcript
m164, which specifies the MHC class I D
d
-restricted peptide 257-AGPPRYSRI-265 defining a pro-
posed second immunological checkpoint.
c
Transcriptional reactivation and virus recurrence after
global immune cell depletion. Absence of immune sensing by CD8 T cells allows desilencing of
viral genomes to proceed to open viral chromatin structure at all essential loci, including the origin
of replication, OriLyt, which leads to recurrence of infectious virions (
virion symbol
).
NC
nuclear
compartment,
CYC
cytoplasmic compartment,
ECC
extracellular compartment.
Black arrowhead
,
position of ORF
m01
.
Green, yellow, blue, and red wavy lines
symbolize IE1, IE3, m164, and down-
stream further transcripts, respectively. The mutation in the IE1 transcript is marked by a
red dot
.
Green, blue, and red triangles
symbolize the corresponding antigenic peptides presented by the
respective MHC class I molecules to cognate T cell receptors
