Biology Reference
In-Depth Information
Interstrain Differences in Cell Tropism
The idea that HCMV strains may differ regarding their reproductive potential in
certain cell cultures was already reported in 1980 (Albrecht and Weller 1980). The
finding that extended propagation in fibroblasts regularly results in loss of endothe-
lial cell tropism, whereas propagation in endothelial cells maintains a broad cell
tropism of the respective strain (Waldman et al. 1991), made the issue of cell
tropism accessible to further experimental analyses. Indeed, the phenotypic differ-
ences are very pronounced with a 100- to 1,000-fold reduction in endothelial cell
tropism of fibroblast-adapted strains irrespective of the origin of endothelial cells
(Kahl et al. 2000; Sinzger et al. 2000). Nevertheless, even severely fibroblast-
adapted strains, such as AD169 or Towne, can infect endothelial cells to some
extent, which may also depend on the origin of the endothelial cell culture. In
consideration of this, such HCMV strains are more precisely classified as poorly
endotheliotropic rather than nonendotheliotropic.
Interstrain differences in HCMV cell tropism occur as a cell culture artifact, but
significant variation has also been described between recent clinical isolates from
different patients (Sinzger et al. 1999b). Together with the finding that multiple
isolates from the same patient behaved identically with regard to endothelial cell
tropism, this suggests a natural interhost variability of HCMV cell tropism. This
may contribute to the highly variable clinical course of HCMV infections in various
patients (Sinzger et al. 1999b). This notion is further supported by the fact that a
high endothelial cell tropism is apparently associated with high infection efficiency
also in monocyte-derived macrophages and dendritic cells, cells that are all assumed
to mediate hematogenous dissemination of HCMV (Jahn et al. 1999).
Viral Genes and Proteins Contributing to Cell Tropism
Restriction fragment analyses of differentially propagated HCMV strains showed
that the restriction of cell tropism during fibroblast adaptation is associated with
multiple genetic modifications (Sinzger et al. 1999b). The introduction of BACmid
technology and subsequent screening procedures for the effect of genetic deletions
led to the identification of several open reading frames involved in endothelial cell
and leukocyte tropism. Dunn et al. found that the residual endothelial cell tropism
of HCMV strain Towne is further reduced by deletion of the viral tegument UL24-
protein, a member of the US22 gene family (Dunn et al. 2003). The highly endothe-
liotropic phenotype of an endothelial propagated strain was found to depend on the
UL128-131 gene region (Hahn et al. 2004). Deletion of either open reading frame
within this region strongly reduced endothelial cell tropism, epithelial cell tropism,
dendritic cell tropism and the virus transfer rate to granulocytes (Hahn et al. 2004;
Wang and Shenk 2005a). UL128, UL130 and also UL131 were found in complex
with glycoproteins gH and gL within virion particles (Wang and Shenk 2005b;
