Bicyclams, a class of potent anti-HIV agents, are targeted at the HIV coreceptor Fusin/CXCR-4
Introduction
The bicyclams are a novel class of highly potent antiviral compounds which selectively inhibit the replication of HIV-1 and HIV-2 (De Clercq et al., 1992, De Clercq et al., 1994). Time-of-addition experiments have indicated that the bicyclams block an early step in the viral replication cycle (De Clercq et al., 1992, De Clercq et al., 1994). Binding studies confined the inhibitory effect on an event following binding, but preceding reverse transcription. AMD3100, previously called JM3100 (De Clercq et al., 1994) or SID791 (De Vreese et al., 1996a, De Vreese et al., 1996b), blocks syncytium formation at a concentration 10–100-fold higher than the concentration required to inhibit virus infection (De Clercq et al., 1992). The envelope gp120 glycoprotein has been considered as the major target molecule for this class of compounds because a number of mutations accumulate in the gp120, especially in the V3–V4 region of viruses that were rendered resistant to the bicyclams (De Vreese et al., 1996a, De Vreese et al., 1996b). The V3 loop is important in the viral fusion process and because recently the gp120 of M-tropic viruses has been demonstrated to interact with CCR-5 (Trkola et al., 1996, Wu et al., 1996), experiments were performed to verify whether AMD3100 did not interact with CCR-5 or with fusin (Berson et al., 1996, Feng et al., 1996), recently named CXCR-4 (Mackay, 1996), the coreceptor for T-tropic HIV-1 and HIV-2 strains.
Section snippets
Isolation and infection of lymphocytes
Buffy coat preparations from healthy donors were obtained from the Blood Bank in Leuven and kindly provided by Dr O. Souw. Peripheral blood mononuclear cells (PBMC) were isolated by density gradient centrifugation over Lymphoprep™ (d=1.077 g/ml) (Nycomed, Oslo, Norway). The cells were stimulated with phytohaemagglutinin (PHA) at 1 μg/ml (Wellcome) for 3 days at 37°C. The activated cells (PHA blasts) were washed three times with phosphate buffered saline (PBS), pelleted and incubated with HIV (1
Results
The monoclonal antibody (mAb), 12G5, reacts specifically with the human fusin protein and recognizes the protein on many T-cell lines such as the SUP-T1 cells (Endres et al., 1996). As shown in Fig. 1, AMD3100 at 25 μg/ml completely inhibited the binding of the 12G5 mAb to CXCR-4 on SUP-T1 cells. This is in contrast with two other potent HIV inhibitors, the sulfated polysaccharide dextran sulfate (DS) (Baba et al., 1990) and the oligonucleotide AR177, also called T30177 or Zintevir (Ojwang et
Discussion
Our data demonstrate that the bicyclam AMD3100 strongly interacts with CXCR-4, whereas DS and AR177, two other compounds that also interfere with virus entry into the cells (and interfere with virus binding), do not. AMD3100 is a unique compound in that it interferes with the chemokine receptor CXCR-4. AMD3100 does not appear to interact with CCR-5, or other CC chemokine receptors, as monitored by its inability to prevent the binding of biotinylated MIP-1α or biotinylated RANTES to SUP-T1
Acknowledgements
We thank Sandra Claes and Erik Fonteyn for their excellent technical assistance. We are grateful to Dr James A. Hoxie for kindly providing the 12G5 mAb. This work was supported by grants from the Fonds voor Wetenschappelijk Onderzoek Vlaanderen, the Belgian Geconcerteerde Onderzoekacties, the Belgian Fonds voor Geneeskundig Wetenschappelijk Onderzoek and the Janssen Research Foundation. J.A. Esté is a fellow from BID-CONICIT (Venezuela).
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