Inhibition of T-tropic HIV Strains by Selective Antagonization of the Chemokine Receptor CXCR4

Abstract

Bicyclams are a novel class of antiviral compounds that are highly potent and selective inhibitors of the replication of HIV-1 and HIV-2. Surprisingly, however, when the prototype compound AMD3100 was tested against M-tropic virus strains such as BaL, ADA, JR-CSF, and SF-162 in human peripheral blood mononuclear cells, the compound was completely inactive. Because of the specific and potent inhibitory effect of AMD3100 on T-tropic viruses, but not M-tropic viruses, it was verified that AMD3100 interacts with the CXC-chemokine receptor CXCR4, the main coreceptor used by T-tropic viruses. AMD3100 dose dependently inhibited the binding of a specific CXCR4 monoclonal antibody to SUP-T1 cells as measured by flow cytometry. It did not inhibit the binding of the biotinylated CC-chemokine macrophage inflammatory protein (MIP) 1α or MIP-1β, ligands for the chemokine receptor CCR5 (the main coreceptor for M-tropic viruses). In addition, AMD3100 completely blocked (a) the Ca2+ flux at 100 ng/ml in lymphocytic SUP-T1 and monocytic THP-1 cells, and (b) the chemotactic responses of THP-1 cells induced by stromal cell–derived factor 1α, the natural ligand for CXCR4. Finally, AMD3100 had no effect on the Ca2+ flux induced by the CC-chemokines MIP-1α, regulated on activation normal T cell expressed and secreted (RANTES; also a ligand for CCR5), or monocyte chemoattractant protein 3 (a ligand for CCR1 and CCR2b), nor was it able to induce Ca2+ fluxes by itself. The bicyclams are, to our knowledge, the first low molecular weight anti-HIV agents shown to act as potent and selective CXCR4 antagonists.

Inhibition of HIV-1 fusion with small interfering RNAs targeting the chemokine coreceptor CXCR4

“…A variety of antibodies, small molecular inhibitors and intracellular single-chain variable fragments (SFvs) have been used both in vitro, and some in vivo, to inhibit CXCR4-specific binding of HIV-1 in relevant target cells. [39][40][41][42][54][55][56][57][58][59][60] Of note, the in vivo-tested molecular inhibitors of CXCR4 did not appear to lead to significant adverse immunological effects. 42 In addition, targeting cellular proteins that act as cofactors in the HIV-1 life cycle may be of greater reliability than targeting viral mRNA species or genomic RNA with RNAi, as the propensity of this virus to undergo rapid mutations would alter the long-term inhibitory capabilities of siRNAs directed against the virus itself.…”

Lentiviral transduction of human T-lymphocytes with a RANTES intrakine inhibits human immunodeficiency virus type 1 infection

“…37 Moreover, there have been several reports of using small molecules or chemokines to block HIV-1 infection and to decrease viral load in HIV-infected individuals. [38][39][40][41] Hence, targeting HIV-1 co-receptors to block virus entry is a reasonable approach to the control of HIV-1 infection, thus warranting further evaluation in animal model and human trials.…”

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

“…After the discovery of the co-receptor function of CXCR4 for T tropic HIV-1, the specific CXCR4-blocking function of the different CXCR4 antagonists was rapidly demonstrated. [66][67][68] With the rapid increase in our knowledge of other, non-HIV-related functions of CXCR4 over the past 11 years, other potential applications such as HSC mobilization and treatment of cancer and autoimmune disease are emerging and have gradually replaced the original intent to use CXCR4 antagonists as anti-HIV drugs.…”