Biology Reference
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the rhesus macaque models, have provided data consistent with proposed mecha-
nisms of immune-mediated protection from HCMV in the human host (Baroncelli
et al. 1997; Kuhn et al. 1999; Podlech et al. 2000; Kaur et al. 2002, 2003; Reddehase
et al. 2002; Barry et al. 2006; Holtappels et al. 2006). The critical importance of
virus-specific CD4
+
and CD8
+
lymphocyte responses, and in some cases antiviral
antibodies, to protective immunity is mirrored by observational studies in human
allograft recipients and HIV-infected individuals (Reusser et al. 1991, 1997; Walter
et al. 1995; Schoppel et al. 1998b; Sester et al. 2001). Natural killer cell responses
have been demonstrated to play a major role in host resistance in mice infected with
MCMV, and studies in this system have provided insights into the biology of
NK cell receptors as well as the genetic control of NK responses in mice (Scalzo
et al. 1992; Polic et al. 1998; Biassoni et al. 2001; Moretta et al. 2001; Krmpotic
et al. 2002; Yokoyama and Scalzo 2002; French and Yokoyama 2003; Lodoen et al.
2003; Voigt et al. 2003; Bubic et al. 2004; French et al. 2004; Hasan et al. 2005;
Adam et al. 2006). Although presumed to be of similar importance in humans, the
evidence implicating NK responses in protective responses of humans infected with
HCMV is more limited (Bowden et al. 1987; Biron et al. 1989; Lopez-Botet et al.
2001; Iversen et al. 2005; Wills et al. 2005; Cook et al. 2006; Prod'homme et al.
2007; Wagner et al. 2007). The importance of HCMV as an opportunistic pathogen
in HIV-infected patients prior to the availability of active antiretroviral therapy
(ART) provided new insights into the relationship between HCMV and the immune
system. Several important concepts were derived from the myriad of studies of
HCMV infection in patients with AIDS, including the observation that seemingly
minimal adaptive cellular immunity was sufficient for the control of virus replica-
tion and the maintenance of the homeostasis between host and virus (Autran et al.
1997; Komanduri et al. 2001a, 2001b). Secondly, technologies developed to study
cellular immune responses to HCMV in these patients indicated that even in
normal individuals, the host immune system has allocated an unexpectedly large
proportion of circulating T lymphocytes to the recognition of HCMV-infected
cells (Waldrop et al. 1997; Sylwester et al. 2005). With the apparent limited
pathogenicity of HCMV based on studies in both normal individuals and those
with treated HIV infection, it is perplexing why the host has dedicated so much
of its T lymphocyte response to this single virus. It has been difficult to reconcile
that in some normal immunocompetent individuals up to 10% of their circulating
T lymphocytes are HCMV-specific in light of the limited pathogenicity of this
virus in all but the most immunocompromised hosts (Jin et al. 2000; Sester et al.
2002a, 2002b; Sylwester et al. 2005). Furthermore, understanding mechanisms of
HCMV persistence in the normal host even in the face of the exuberant host
immune response remains a major question in viral immunology. A frequently
invoked explanation for this apparent paradox is that the complex network of
viral genes that encode immune evasion functions and facilitates persistent infec-
tion with this virus have been countered by an exaggerated host T lymphocyte
response. Whether this so-called memory expansion of T lymphocyte responses
is provoked by continual low-level replication or frequent reactivations from
latency is unknown. Studies in experimental animal models have provided data
