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Compton 1997; Raynor et al. 1999). Antiserum against annexin II was also able
to inhibit plaque formation in fibroblasts; however, cells lacking annexin II are
completely permissive for HCMV infection (Wright et al. 1995; Pietropaolo and
Compton 1999). Therefore, it is unlikely that annexin II is an HCMV entry recep-
tor, but may enhance entry, cell-to-cell spread, and/or viral egress.
It was discovered that peripheral blood mononuclear cells that expressed CD13
(human aminopeptidase N), were permissive for HCMV infection (Soderberg
et al. 1993b; Larsson et al. 1998). Antibodies to CD13 inhibited infection as well
as virus attachment to cells but it was later determined that these antibodies also
prevented entry into CD13-null cells when the antibody was incubated with the
virus, suggesting that the antibodies are binding directly to HCMV virions.
(Soderberg et al. 1993a; Larsson et al. 1998). Although CD13 may not be involved
in virus entry, it was recently discovered that an HCMV-CD13 interaction inhibits
macrophage differentiation from monocytes (Gredmark et al. 2004).
A 92.5-kDa cellular receptor for HCMV was identified for gH through the use
of anti-idiotype antibodies that bear the image of gH and are able to specifically
bind the 92.5-kDa protein (reviewed in Keay and Baldwin 1995). These antibodies
inhibit plaque formation but not virus attachment to cells (reviewed in Keay and
Baldwin 1995). The 92.5-kDa receptor has been identified as a phosphorylated
glycoprotein that mediates a release of intracellular calcium upon virus binding
(reviewed in Keay and Baldwin 1995; reviewed in Keay et al. 1995). Partial cloning
and sequencing of the 92.5-kDa receptor have not revealed homology to any known
protein; therefore, its identity remains unknown (Baldwin et al. 2000).
More recently, both the epidermal growth factor receptor (EGFR) and a
specific subset of cellular integrins have been identified as HCMV entry and
signaling receptors. It was noticed that many downstream signaling events
initiated by HCMV, including Akt, phosphatidylinositol-3-OH kinase, and phos-
pholipase C-γ activation, as well as the mobilization of intracellular Ca
2+
, are
indicative of EGFR activation (Wang et al. 2003). It was demonstrated that
HCMV robustly activates the EGFR kinase, suggesting that EGFR acts at least as
a signaling receptor for HCMV (Wang et al. 2003). It was also noted that HCMV
initiates gene expression in a breast cancer cell line overexpressing EGFR, but
gene expression was not detectable in another EGFR-null cell line (Wang et al.
2003). Additionally, a specific EGFR kinase inhibitor blocked HCMV gene
expression in the EGFR-expressing cell line (Wang et al. 2003). The first con-
crete evidence that EGFR may act as an entry receptor was that in fibroblasts an
EGFR neutralizing antibody inhibited HCMV attachment and entry (Wang et al.
2005). Last, the authors demonstrated through cross-linking experiments that
HCMV gB can interact with EGFR (Wang et al. 2003). These results were excit-
ing, as the major receptor for HCMV entry had yet to be discovered, with the
exception of cellular integrins, whose contribution to virus entry was being
examined at the same time as EGFR was proposed to be an entry receptor.
However, it was also known that EGFR, although widely expressed, is not found
on all cell types permissive for HCMV infection, including hematopoietic cells,
suggesting that EGFR may not be a universal receptor for HCMV (Real et al.
