Fusion Mediated by the HIV-1 Envelope Protein - Fusion of Biological Membranes and Related Problems - page 463

while T-tropic viruses enter T-cell lines and primary T-cells, but often fail to
enter macrophages (Schuitemaker et al., 1992). This differential tropism is
clinically important, since M-tropic virus strains are largely responsible for
virus transmission and are the most common type of virus isolated from
asymptomatic individuals (Roos et al., 1992; Schuitemaker et al., 1992; Zhu
et al., 1993), while T-tropic viruses tend to emerge (as a consequence of
mutations in Env) after a period of years (Tersmette et al., 1989; Tersmette
et al., 1989). Emergence of T-tropic virus strains is associated with acceler-
ated progression to AIDS (Connor et al., 1993; Schuitemaker et al., 1992;
Tersmette et al., 1989; Tersmette et al., 1989). Taken together, these obser-
vations indicate that HIV requires, in addition to CD4, a coreceptor to
infect cells, and that M-tropic and T-tropic virus strains might utilize dif-
ferent coreceptors. Since the block to virus infection in the absence of
a coreceptor is at the level of membrane fusion, coreceptors are likely
to serve as the “trigger” that enables Env to undergo the conformational
changes needed to mediate membrane fusion.
After a number of false leads, the first bona-fide HIV coreceptor was
identified by Berger and colleagues in 1996, and was initially called Fusin
for its ability to facilitate viral fusion and entry by T-tropic (but not M-
tropic) virus strains (Feng et al., 1996). Fusin, a 46 kD transmembrane
glycoprotein, was later found to be a member of the chemokine receptor
family of G-protein coupled seven transmembrane spanning proteins
(Bleul et al., 1996; Oberlin et al., 1996). The chemokine receptors serve as
receptors for chemoattracant cytokines which are involved in leukocyte
transmigration and inflammation (reviewed in Rollins, 1997). Chemokines
are named based on the position of their N-terminal cysteines with or
without intervening amino acids and this corresponds to the receptor names
which include the C-C, C-X-C, C, and C-X3-C receptors. The receptor
termed Fusin was then named CXCR4 as it is a receptor for the CXC
chemokine stromal-derived factor-1 (SDF-1). Numerous studies have
shown that while CXCR4 is a coreceptor for T-tropic virus strains, it fails
to support infection by M-tropic viruses (Berson et al., 1996; Feng et al.,
1996). Introduction of CXCR4 and CD4 into almost any cell type renders
the cell permissive to T-tropic but not M-tropic Env-mediated membrane
fusion.
CXCR4 is expressed on a variety of cells including monocytes, neu-
trophils and lymphocytes and a variety of T cell lines (Bleul et al., 1997;
Forster et al., 1998; Hesselgesser et al., 1998; Ostrowski et al., 1998). Com-
pared to CCR.5, CXCR4 is expressed preferentially on the CD45RA + subset
of activated memory T-cells, while CCR.5 is expressed preferentially on
CD45RO + T-cells (Bleul et al., 1997). Macrophages also express abundant
levels of CXCR4 (Lee et al., 1999), though there is considerable donor