Biology Reference
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et al. 1999; Stals 1999; Barry et al. 2006). More severe infections with significant
end-organ dysfunction have been related to the inoculum size in experimental
animals and also in humans following inoculation of vaccine trial volunteers with
a clinical virus isolate (Plotkin et al. 1989; Bernstein 1999; Kern 1999). Following
human infection acquired by exposure of mucosal sites, it is presumed that local
replication occurs and the primary viremia leads to spread from these sites to other
sites of virus amplification such as the liver and/or spleen. Studies in experimental
animals have utilized parenteral inoculations in most cases; however, descriptions
of infections following oral inoculations have been reported in both mice and
nonhuman primates (Lockridge et al. 1999) (S. Jonjic, personal communication).
Because the manifestations of infection and dissemination after oral infection are
similar to those of parenteral infection, it is likely that virus first replicates locally
regardless of site or route of inoculation and then spreads to visceral sites such as
the liver, lung, and spleen where it further amplifies. It is likely that visceral organs
serve as reservoirs for infectious virus during acute infections and presumably
dissemination to other organs takes place, depending on the immune status of the
host. Virus is cleared over a period of weeks to months as measured by the presence
of virus or viral DNA in peripheral blood. In the mouse and guinea pig (and
presumably in humans), persistent viral infection is established in the salivary
gland within 2 weeks after infection and virus can be recovered from this organ
long after replicating virus has been cleared from the blood as well as the liver and
spleen (Bernstein 1999; Kern 1999).
The relative contribution of cell-free vs cell-associated virus to either the primary
or secondary viremia following HCMV infection has not been fully defined.
Several possible mechanisms for virus dissemination in the vasculature have been
proposed and explored experimentally. Viral genes responsible for the extended
cellular tropism of clinical viral isolates as compared to laboratory passaged viruses
have been identified (Percivalle et al. 1993; Gerna et al. 2000; Hassan-Walker et al.
2001; Hahn et al. 2004; Wang and Shenk 20054a, 2005b). Specific cellular tropism
of HCMV appears to be an important determinant in the spread of this virus within
the infected host (MA et al. 2006). Cell-free virus transmission during dissemina-
tion is thought to be unlikely because HCMV replication is highly cell-associated
and infectious virus is recovered only rarely from cell-free serum or plasma and
then usually only in severely immunocompromised patients with extremely large
amounts of virus in the peripheral blood (Lathey et al. 1994). HCMV DNA can
often be detected in plasma by PCR in this latter group of patients (Boivin et al.
1998; Caliendo et al. 2001). Interestingly, cell-free virus is commonly found in
body fluids such as urine, saliva and breast milk and often at high titers, indicating
that cell-free virus is readily released depending on the site of infection. Early studies
suggested that infected endothelial cells that detach from infected vessels and/or
polymorphonuclear (PMN) leukocytes could carry HCMV to distal sites (Percivalle
et al. 1993; Gerna et al. 1998; Sinzger et al. 1999a; Gerna et al. 2000). Undoubtedly,
infected endothelial cells carry infectious virus but because of their size and proba-
ble limited half-life in the circulation, these cells would be rapidly cleared and less
