Biology Reference
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presumably be expressed at the same time as the known immune evasion genes of
HCMV, which inhibit CTL recognition of virus-infected cells (Tomazin et al. 1999;
Alcami and Koszinowski 2000; Gewurz et al. 2001; Scalzo et al. 2007).
Using the mouse model, Holtappels and co-workers have provided evidence
that immune evasion genes encoded by MCMV m04, m06 and m152 cannot over-
come the CTL response to a peptide encoded by m164, even though the immune
evasion genes could blunt the response to the immunodominant pp89 target
peptide (Holtappels 2002). They have suggested that the m164 target peptide over-
comes the immune evasion system simply by being present in saturating quantities
in infected cells and thus remaining as a target peptide that can be presented to
CTL (Holtappels 2002). The observation that the viral immune evasion functions
do not significantly alter CD8 T cell priming in vivo has been further supported in
studies utilizing a large number of MCMV antigens to examine CD8 T cell immu-
nodominance over time in infected mice (Munks et al. 2007). Together with
findings that CTL specific for the products of the m83 and m84 can provide pro-
tection from lethal MCMV infection in the mouse, even though these viral proteins
do not induce dominant CTL responses, it was argued that a polyclonal CTL
response to MCMV is generated and that this response can be protective even in the
presence of virus-encoded immune evasion functions, an interpretation consistent
with the limited pathogenicity of CMVs in the normal, immunocompetent host.
Similar studies in humans have shown that even in the presence of known immune
evasion functions encoded by US2,3,6, and 11 of HCMV (see the chapter by
C. Powers et al., this volume), a broad CD8
+
cytotoxic T lymphocyte response was
generated in immunocompetent individuals (Manley et al. 2004; Khan et al. 2005).
The role of the immune modulatory functions of HCMV, immune evasion, and the
focusing of the CTL responses continue to merit additional investigation. What
is clear is that under normal circumstances, the host CTL response is sufficient to
protect from uncontrolled virus replication in the presence of virus-encoded
immune evasion functions and that exogenous immune suppression of host
responses of significant magnitude can tip the balance in favor the virus. Finally,
it should be emphasized that antiviral antibodies, particularly virus-neutralizing
antibodies, almost certainly play a role in the protective immune response to CMV.
Passive administration of virus-neutralizing antibodies can protect immunocompro-
mised mice from disseminated MCMV infection and disease (Jonjic et al. 1994).
Likewise studies in bone marrow and solid organ allograft recipients have demon-
strated that passive administration of antiviral antibodies can protect from disease
and that the quantity of virus neutralizing activity correlates with protection
(Snydman et al. 1987; Schoppel et al. 1997, 1998a). Previous studies have argued
that antibodies induced by gB (UL55), the gH/gL/gO complex (UL75,115,74) and
the gM/gN (UL100,73) represent the bulk of virus-neutralizing antibodies in
humans, whereas in the mouse only anti-gB antibodies appear protective (Rapp et
al. 1992; Britt and Mach 1996). Studies in guinea pigs and rhesus macaques have
also identified gB as target of virus-neutralizing antibodies (Britt and Harrison 1994;
Kropff and Mach 1997).
