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1997; Granelli-Piperno et al., 1996; Rubbert et al., 1998; Zaitseva et al., 1997)
but immature DC, cultured from cord blood CD34
cells, were found to be
positive for only CCR5 (Canque et al., 1996). Culturing of DC can in¯uence
their expression of chemokine receptors, and therefore in situ analysis is useful
in determining the expression pattern of these HIV-1 coreceptors. These data
suggest that HIV-1 coreceptor usage of cervical or vaginal DC is di¨erent from
that observed in skin- and monocyte-derived DC, and that care must be taken
in drawing conclusions regarding sexual transmission of HIV-1 from models
using skin- or blood-derived DC. Similar striking results were obtained when
DC in mucosal tissues, such as cervix, rectum and, uterus, were analyzed for the
in situ expression of CD4 as well as CCR5: DC of the lamina propria expressed
CD4 but lacked CCR5, strongly suggesting that DC, present at these sites of
®rst contact with sexually transmitted HIV-1, do not mediate viral fusion and
thus can not be infected by HIV-1.
Recently, we have identi®ed the DC-speci®c HIV-1 trans-receptor DC-
SIGN, through its high-a½nity interaction with ICAM-3 (Geijtenbeek et al.,
2000a). DC-SIGN is a C-type lectin that binds the HIV-1 gp120 protein.
Monocyte-derived DC express high levels of DC-SIGN and intermediate levels
of CD4 and CCR5 (Fig. 11.3A). HIV-1 gp120 binding to immature DC is
completely mediated by DC-SIGN, and not by CD4/CCR5 as was measured
by ¯ow cytometry with the ¯uorescent bead gp120-binding assay ( Fig. 11.3B±
D). However, DC-SIGN does not function as a classical HIV-1 receptor inas-
much as it does not mediate HIV-1 entry (Curtis et al., 1992; Geijtenbeek et al.,
2000a), as do CD4, CCR5, and CXCR4. We have demonstrated that DC-
SIGN binds both M- and T-tropic HIV-1, but also promotes e½cient infection
in trans of cells that express CD4 and the appropriate coreceptors. The function
of DC-SIGN as a trans-receptor is independent of the coexpression of CD4 and
HIV-1 coreceptors. DC-SIGN is abundantly expressed on both monocyte- and
CD34
-derived DC, as well as in vivo dermal DC of the skin and mucosal
tissues involved in sexual HIV-1 transmission (Geijtenbeek et al., 2000a). DC-
SIGN is also speci®cally expressed on two DC precursors in blood that are
CD14
ÿ
and CD14
(Geijtenbeek et al., 2000c). DC-SIGN is abundantly ex-
pressed in vivo by DC present in the rectal, cervical, and uterine mucosa, and,
in contrast, these DC lack CCR5. DC-SIGN may therefore play a crucial role
in initial HIV-1 exposure by mediating HIV-1 binding to DC present in mu-
cosal tissues, rather than infection of these cells.
DIRECT INFECTION OF DC WITH HIV-1?
Data regarding the capacity of DC to support viral replication are con¯icting,
ranging from resistance (Cameron et al., 1992a; Pinchuk et al., 1994; Weissman
et al., 1995a) or nonproductive infection (Cameron et al., 1994; Granelli-
Piperno et al., 1995; Tsunetsugu-Yokota et al., 1997) to productive infection
with both M- and T-tropic strains ( Blauvelt et al., 1997; Dittmar et al., 1997;
Granelli-Piperno
et
al.,
1995;
Tsunetsugu-Yokota
et
al.,
1997).
Immature
