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likely to efficiently disseminate virus widely in the host (Pooley et al. 1999). The
presence of these cells may be more reflective of the severity of an acute infection,
a finding consistent with the observation that such cells are detectable almost exclu-
sively in only the most severely immunocompromised patients (Gerna et al. 1998;
Kas-Deelen et al. 2000). Similarly, many investigators have suggested that PMN
leukocytes may efficiently disseminate HCMV to distal sites, a hypothesis based on
clinical observations of the transmissibility of HCMV from blood cells found in the
buffy coat of peripheral blood (Gerna et al. 2000; Saez-Lopez et al. 2005). This
hypothesis is also consistent with recent studies that have demonstrated that HCMV
infection not only upregulates IL-8 expression but encodes an IL-8 like molecule,
the UL146/vCXC-1, (Grundy et al. 1998; Penfold et al. 1999; Redman et al. 2002).
Because IL-8 is a chemoattractant for neutrophils, infected cells could recruit
PMN into the foci of infected cells and disseminate infectious virus passively
acquired by the PMN. Results from studies in mice infected with MCMV are
consistent with such a mechanism (Saederup et al. 1999; Noda et al. 2006). Lastly,
cells of the monocyte/macrophage lineage can be infected with HCMV and thus
could serve to disseminate HCMV (Taylor-Wiedeman et al. 1991, 1994; Kondo
et al. 1996; Soderberg-Naucler et al. 1997; Bolovan-Fritts et al. 1999). Interestingly,
studies in immunocompromised patients suggest that circulating monocytes
contain quantitatively a similar number of viral genomes as PMN, suggesting that
cells of this lineage may disseminate the HCMV as efficiently as PMN (Hassan-
Walker et al. 2001).
End-organ disease following acute infection has been most closely correlated
with virus replication and virus-induced cytopathology, suggesting that organ
dysfunction and cellular damage are likely related to the lytic replicative cycle of
the virus in most cell types found in every organ system, with the possible exception
of the CNS. Observations from animal models are consistent with this proposed
mechanism of disease, and disease appears to correlate with levels of replicating
virus (Persoons et al. 1998; Kern 1999; Podlech et al. 2000). The mechanism of cell
death following lytic infection is not well understood; however, lytically infected
human fibroblasts develop significant morphologic changes, including a marked
increase in the size of the nucleus, nuclear and cytoplasmic inclusions, blebbing
and focal loss of nuclear membrane integrity, displacement of normal cellular
secretory pathway organelles with virus assembly sites, and eventually disruption
of the plasma membrane. In some cell types, productive infection appears to be
nonlytic (Fish et al. 1998). Apoptosis is not a prominent component of the early
cellular response to CMV infection and at least in the case of HCMV, anti-apoptotic
functions encoded by several viral genes inhibit this cellular response (Goldmacher
2002; McCormick et al. 2003; Andoniou and Degli-Esposti 2006; Sharon-Friling
et al. 2006). In addition, recent findings indicate that HCMV encodes viral functions
that inhibit innate cellular responses to virus infection such as nuclear responses to
viral DNA shortly after infection, induction of PKR and phosphorylation of eIF2-
and activation of RNAase L (Child 2002; Cassady 2005; Hakki and Geballe 2005;
Cantrell and Bresnahan 2006; Child et al. 2006; Hakki et al. 2006; Saffert and
Kalejta 2006). Murine CMV has been shown to encode similar functions (m142
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