Promising anti-HIV therapeutic strategy with a small molecule CXCR4 antagonist

The discovery that HIV requires a chemokine receptor to invade host cells has prompted investigations into therapeutic strategies that target these receptors in an attempt to block HIV entry. With the prototype compound of the bicyclams, AMD3100, we were recently able to show that it is possible to obtain a small and very specific antagonistic molecule for CXCR4, the main coreceptor used by T-tropic, SI isolates of HIV. It binds to a conserved region of CXCR4 and by doing this potently prevents viral infection. CXCR4 antagonists, such as AMD3100, can be a powerful approach as an immunotherapeutic strategy to slow down disease progression in AIDS, because a coreceptor switch in viral isolates from CCR5 (mainly used by M-tropic, NSI isolates of HIV) to CXCR4 occurs when patients progress towards AIDS. Moreover, AMD3100 is also able to block as efficiently dual-tropic viruses (which use equally well CCR5 and CXCR4) as pure T-tropic viruses in human PBMC, indicating that CXCR4 is the predominant coreceptor for infection of these cells.