Biology Reference
In-Depth Information
T A B L E
1.2. HIV Cell Receptors and Their Natural Ligands
CD4
CCR5
CXCR4
CCR3
CCR2b
BOB
BONZO
HIV
NSI
ÿ
SI
()
Natural ligands
MHC
MIP-1a
SDF-1
RANTES
MCP-1
?
?
Cl. II
MIP-1b
MCP-3
MCP-2
RANTES
EOTAXIN
MCP-3
MCP-4
NSI, nonsyncytium inducing; SI, syncytium inducing.
tion is of crucial importance for understanding the natural history of this in-
fection and developing e¨ective anti-HIV strategies. In particular, the envelope
glycoproteins of HIV-1 interact with receptors of the target cells and mediate
the process of virus entry. This process is complex, including binding of the
viral gp120 to CD4, conformational changes of the viral glycoprotein, and
subsequent use of a coreceptor before gp41-mediated fusion of the viral enve-
lope and the cellular membrane (Kwong et al., 2000; Rizzuto and Sodroski,
2000; Rizzuto et al., 1998; Wu et al., 1996; Wyatt et al., 1995; Zhang et al.,
1999) (Table 1.2). The evolutionary changes characterizing the HIV-1 popula-
tion during the natural history of infection strongly in¯uence crucial regions
of the viral env gene (Bagnarelli et al., 1999; Menzo et al., 1998; Salvatori et
al., 1997; Scarlatti et al., 1997; Shankarappa et al., 1998, 1999; Wolinsky et al.,
1996). Because di¨erent variable domains of the HIV-1 gp120 play a key role in
driving the early steps of the viral infection cycle, including coreceptor usage
( Isaka et al., 1999; Sato et al., 1999; Verrier et al., 1999; Xiao et al., 1998) and
CD4 independence ( LaBranche et al., 1999), careful analysis of the intrahost
evolution of the HIV-1 env gene is strategic for addressing the relevant features
of the virus-host relationships (Yamaguchi and Gojobori, 1997; Yamaguchi-
Kabata and Gojobori, 2000). In addition, HIV entry is at present an attractive
target for new classes of antiretroviral compounds (Sodroski, 1999); at present,
these compounds include inhibitors of HIV binding to CCR5 and CXCR4
coreceptors and fusion inhibitors (Murakami et al., 1999; Ono et al., 1997;
Sakaida et al., 1998; Torre et al., 2000).
The V3 sequence is a variable domain in the HIV gp120 and contains 35
amino acids arranged in a loop. This domain plays a crucial role in driving
important biological properties of the virus, including cell tropism. Generally,
mutations in the V3 loop do not a¨ect the ability of gp120 to interact with the
CD4 receptor, although several studies have unambiguously indicated that V3
sequences play an important role in two correlated biological features with
pathogenic implications, that is, syncytium formation ( Willey et al., 1994) and
