Cytomegalovirus Immune Evasion - Human Cytomegalovirus - page 330

MHC-I alleles (Thammavongsa et al. 2006). US3 was shown to preferentially retain
tapasin-dependent MHC-I alleles by inhibiting their acquisition of high-affinity peptides,
whereas tapasin-independent alleles were not affected (Park et al. 2004). The same group
recently identified a critical role of PDI in stabilizing the peptide-receptive site of MHC-I
by regulating the oxidation of the α2 disulfide bond in the peptide-binding groove (Park
et al. 2006). Interestingly, PDI protein levels were decreased in the presence of US3 and
a complex between US3 and PDI is stabilized by proteasome inhibitors. By degrading
PDI, US3 inhibits the binding of high-affinity peptides to tapasin-dependent alleles of
MHC-I. Since PDI and tapasin are part of the peptide loading complex and can be co-
immunoprecipitated, it is likely that previously observed interactions between US3 and
MHC-I or tapasin are the result of US3 entering the peptide loading complex (Park et al.
2006).
MCMV as a Model System for CMV Interference
with MHC-I Expression
MCMV does not encode homologs of the HCMV VIPRs, but encodes its own
VIPRs m04, m06, and m152 (see Fig. 2; recently reviewed in Reddehase et al.
2004; Pinto and Hill 2005). The gp34 protein encoded by m04 does not reduce
MHC-I surface levels but forms a tight association in the ER and accompa-
nies MHC-I to the cell surface (Kleijnen et al. 1997; Kavanagh et al. 2001) where
it is able to inhibit cytotoxic T cell lysis by an unknown mechanism (Pinto and Hill
2005). The m06-encoded gp48 associates with MHC-I and directs this complex to
the lysosomes where both are destroyed (Reusch et al. 1999). Lastly, m152 encodes
gp40, which retains MHC-I in the ERGIC (Ziegler et al. 1997). Interestingly, MHC-
I retention occurs in the absence of a detectable biochemical interaction (Ziegler
et al. 1997; Pinto and Hill 2005). Since HCMV cannot infect immunocompetent
experimental animals, the MCMV VIPR system has been used to determine the role
of MHC-I inhibitors in the context of CMV infection in vivo.
Initial studies in immunocompromised mice have suggested a role for m152/
gp40 in controlling the CD8 + T cell response to the virus and being responsible for
increased viral titers (Krmpotic et al. 1999). It was further demonstrated that m152/
gp40 protected MCMV from adoptively transferred epitope-specific T cells
(Holtappels et al. 2004), the first (and so far only) experiment showing a VIPR
preventing viral peptide presentation in vivo. In contrast, the m152/gp40-deleted
virus induced a CD8 + T cell response to the immunodominant M45 epitope that
was similar to WT-MCMV in C57BL/6 mice (Gold et al. 2002). Moreover, the
CD8 + T cell response to MCMV lacking all three VIPRs was very similar to that
induced by WT (Gold et al. 2004; Munks et al. 2007). An important conclusion
from these studies was that VIPRs do not seem to influence the induction of CD8 +
T cell responses, suggesting that passive presentation of infected cells (cross-pres-
entation) rather than direct presentation of virus-derived peptides by infected cells
induces the T cell response.