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designated by the coreceptor(s) that they use for cellular entry. Hence, viruses
that use either CCR5, CXCR4, or both for entry are now designated R5, X4, or
R5/X4 viruses, respectively (Berger et al., 1998).
CCR5 and CXCR4 also serve as the major coreceptors for HIV-2, whereas
CCR5 is the major coreceptor for simian immunode®ciency virus (SIV ) ( Doms
et al., 1998). Other members of the chemokine receptor family or even other
G-protein coupled receptors (GPCRs) have been ascribed coreceptor activity in
vitro, at least for select viral strains (Choe et al., 1996, 1998; Deng et al., 1997;
Doranz et al., 1996; Edinger et al., 1998; Farzan et al., 1997; Horuk et al., 1998;
Liao et al., 1997; McKnight et al., 1998; Reeves et al., 1997; Rucker et al.,
1997; Samson et al., 1998; Shimizu et al., 2000). However, the in vivo signi®-
cance of these alternate coreceptors remains obscure, as the vast majority of
these isolates are unable to replicate in PBMCs in the presence of CCR5- and
CXCR4-speci®c antagonists (Zhang et al., 2000). The paramount importance
of CCR5 in the pathogenesis of acquired immunode®ciency syndrome (AIDS)
is indicated by genetic-epidemiological evidence that individuals who are
homozygous for a CCR5-null mutation (ccr5D32) are highly resistant to HIV
infection, whereas HIV-infected individuals who are heterozygous for ccr5D32
progress to clinical AIDS more slowly than their homozygous CCR5 wild-type
counterparts (reviewed in Carrington et al., 1999), most likely because of a rel-
atively modest reduction in CCR5 expression (Wu et al., 1997). Indeed, core-
ceptor expression levels can have a signi®cant impact on viral infectivity ( Platt
et al., 1988; Sharron et al., 2000). The presence of a disease progression mod-
ifying allele in the SDF-1 gene (Balotta et al., 1999; Brambilla et al., 2000; John
et al., 2000; Mummidi et al., 1998; van Rij et al., 1998; Winkler et al., 1998),
which codes for the natural chemokine ligand to CXCR4, coupled with the in-
creased pathogenicity of CXCR4-using strains (Schramm et al., 2000) predom-
inantly isolated from patients in later stages of HIV disease also points to the in
vivo importance of CXCR4 in HIV pathogenesis.
The use of CD4 and various coreceptors by the primate immunode®ciency
viruses to enter cells indicates that the expression patterns of these receptors is
of critical importance in governing viral tropism: the ability of a virus strain to
infect some cell types but not others. In addition, because the membrane fusion
process mediated by the viral Env protein is highly cooperative in nature, re-
quiring both multiple Env proteins as well as multiple receptor interactions to
form a fusion pore (Kuhmann et al., 2000), it logically follows that expression
levels of the various receptors will also in¯uence viral infectivity. As a result,
multiparametric FACS analysis of CD4 and coreceptor expression is ideally
suited for studies designed to identify which of the myriad T-cell subsets are
susceptible to infection by any given virus strain. The introduction of rigor-
ous, quantitative FACS techniques, often in conjunction with multiparametric
analyses, has made it possible to identify not just the cell types that express the
receptors needed to support virus infection, but to identify cells that express
these receptors at su½ciently high levels. These approaches are also needed to
dissect the web of cytokine and immune system interactions that in¯uence re-
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