Abstract
The chemokine receptors CXCR4, CCR2b, CCR3, and CCR5 are cell entry coreceptors for HIV-1. Using an HIV-1 envelope (Env)-dependent cell-cell fusion model of entry, we show that CCR3 can interact with Envs from certain macrophage (M)-tropic strains (which also use CCR5), T cell line (TCL)-tropic laboratory-adapted strains (which also use CXCR4), and a dual-tropic primary isolate (which also uses CCR2b, CCR5, and CXCR4). Paradoxically, CCR1 is the closest homologue to CCR3 (63% amino acid identity), but lacked HIV-1 coreceptor activity. These results confirm and extend previous reports. Replacing the N-terminal segment of CCR3 with that of CCR1 abolished activity of the resulting chimera for M-tropic and TCL-tropic Envs, but not for the dual-tropic Env. Replacing extracellular loop 2 of CCR3 with that of CCR1 abolished activity for TCL-tropic Envs, but not for M- and dual-tropic Envs. A chimera containing all four extracellular regions of CCR3 on a backbone of CCR1 lacked any activity. Env-CCR3 interactions were strongly inhibited by the major CCR3 ligand eotaxin, but weakly or not at all by other CCR3 ligands. With primary macrophages, eotaxin induced transient calcium flux and partially inhibited fusion with cells expressing M-tropic Envs. We conclude that specificity determinants for different Envs are located in shared and distinct extracellular regions of CCR3, the transmembrane/cytoplasmic domains make major contributions to coreceptor function, and CCR3 may be used by certain HIV-1 strains as a cell fusion factor on macrophages.
Highlights
The chemokine receptors CXCR4, CCR2b, CCR3, and CCR5 are cell entry coreceptors for HIV-1
Since the extracellular regions of CCR1 and CCR3 contain the majority of amino acid differences between the two molecules (Fig. 2) and are the most likely regions to directly contact envelope glycoprotein gp120 (Env), we switched
We have previously reported that CCR3 mRNA is present in primary macrophages, albeit at very low levels compared with primary eosinophils [27]
Summary
M, macrophages; TCL, T cell lines; RANTES, reduced upon activation normal T cell expressed and secreted; MCP, monocyte chemoattractant protein; CCR, CC chemokine receptor; HIV-1, human immunodeficiency virus-1; Env, envelope glycoprotein of HIV-1; FACS, fluorescence-activated cell sorter. CXCR4 was originally identified as a coreceptor for laboratory-adapted TCL-tropic strains [6], whereas CCR5 functions preferentially for M-tropic primary isolates [7,8,9,10,11]. Involvement of endogenous CXCR4 in HIV-1 infection is supported by the ability of its natural ligand SDF-1 [23, 24] and anti-receptor antibodies [6, 25] to block infection of primary leukocytes with TCL-tropic laboratoryadapted strains in vitro; proof of its importance in people is currently lacking. Recombinant CCR3 has been shown to interact with several primary HIV-1 isolates including dual-tropic and some M-tropic strains [10, 11, 14, 26]. We provide evidence that CCR3 may function as an HIV-1 coreceptor in blood-derived macrophages
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