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produced by individual strains varies because evidence suggests vMIA is an
important regulator of the viral response to stress (McCormick et al. 2005). The
phenotype produced by disruption of vMIA in AD169
var
ATCC is highly variable
(Brune et al. 2003; Yu et al. 2003; Sharon-Friling et al. 2006), perhaps due to other
factors that prevent vMIA-dependent release of calcium from the endoplasmic
reticulum (Sharon-Friling et al. 2006) or increase ATP levels (Poncet et al. 2006),
and further analyses are needed to resolve the role of vMIA in that strain.
Although of limited impact on replication in HFs, the Towne
var
ATCC mutant
revealed a role for vMIA in regulating caspase-independent death. Caspase-3
activation underlies caspase-dependent apoptosis; however, this protease is not
required for other cell death pathways that are considered to be apoptosis-like
(Leist and Jaattela 2001; Lockshin and Zakeri 2002; Jaattela 2004). Thus,
UL37×1 deletion can promote CMV-induced caspase-3-dependent cell death in
the case of AD169
var
ATCC (Reboredo et al. 2004), or a caspase-3-independent
cell death in the case of Towne
var
ATCC (McCormick et al. 2005), and vMIA
regulates both forms of death during infection (McCormick et al. 2005). From
studies so far, the context where caspase-3-independent cell death is a significant
obstacle to the virus is unknown.
Chimpanzee CMV, rhesus macaque CMV, and African green monkey CMV
each retain a vMIA homolog that could be identified through computer analysis
(McCormick et al. 2003a). Each of these proteins share sequence similarity with
the mitochondrial-targeting and AAD domains of vMIA. Rhesus macaque CMV
vMIA retains similarity only to the amino- and carboxyl-terminal domains of
human CMV (HCMV) vMIA and functions as an antiapoptotic protein. It is
expected that all primate CMVs encode functional homologs. In contrast, the
identification of rodent CMV functional homologs encoded by ORFs, m38.5 and
r38.5, required more extensive analyses due to limited sequence homology
(McCormick et al. 2003a, 2005; Brocchieri et al. 2005). Initial searches for
murine CMV (MCMV) mitochondrial localized proteins with vMIA function
were executed in HeLa cells utilizing methods that revealed vMIA (Goldmacher
et al. 1999; McCormick et al. 2003a). Increasing the repertoire of stimuli
revealed that m38.5 prevents proteasome inhibitor-induced, intrinsic apoptosis
but not extrinsic, Fas-mediated apoptosis in HeLa cells (McCormick et al. 2005)
or a telomerase-immortalized retinal epithelial cell line of human origin (Jurak
and Brune 2006). Thus, MCMV m38.5 encodes an antiapoptotic protein that
localizes to mitochondria (McCormick et al. 2005). The rodent CMV ORFs map
to positions on the viral genomes analogous to UL37×1 (McCormick et al.
2003a; Brocchieri et al. 2005), indicating that rodent and primate CMVs each
encode vMIA and vICA homologs.
Limited sequence similarity and differences in protective function in human
cells suggest the human and rodent vMIA homologs retain elements that are
specific to function in the appropriate host (McCormick et al. 2005). Identification
of additional MCMV proteins localized to mitochondria may also suggest the
potential for synergism or even replacement of m38.5 function in specific cells
(Tang et al. 2006). Interestingly, vMIA apparently protects from specific apoptotic
