A Small-molecule Inhibitor Directed against the Chemokine Receptor CXCR4 Prevents its Use as an HIV-1 Coreceptor

Abstract

The chemokine receptor CXCR4 is the major coreceptor used for cellular entry by T cell– tropic human immunodeficiency virus (HIV)-1 strains, whereas CCR5 is used by macrophage (M)-tropic strains. Here we show that a small-molecule inhibitor, ALX40-4C, inhibits HIV-1 envelope (Env)-mediated membrane fusion and viral entry directly at the level of coreceptor use. ALX40-4C inhibited HIV-1 use of the coreceptor CXCR4 by T- and dual-tropic HIV-1 strains, whereas use of CCR5 by M- and dual-tropic strains was not inhibited. Dual-tropic viruses capable of using both CXCR4 and CCR5 were inhibited by ALX40-4C only when cells expressed CXCR4 alone. ALX40-4C blocked stromal-derived factor (SDF)-1α–mediated activation of CXCR4 and binding of the monoclonal antibody 12G5 to cells expressing CXCR4. Overlap of the ALX40-4C binding site with that of 12G5 and SDF implicates direct blocking of Env interactions, rather than downregulation of receptor, as the mechanism of inhibition. Thus, ALX40-4C represents a small-molecule inhibitor of HIV-1 infection that acts directly against a chemokine receptor at the level of Env-mediated membrane fusion.

Modulation of CXCR4 expression and SDF-1α functional activity during differentiation of human monocytes and macrophages

“…The novel finding that CXCR4 is transcriptionally and functionally re-expressed in mature macrophages is particularly interesting because it would indicate a role for SDF-1 during the inflammatory response to vascular injury, in addition to its earlier proposed function in immune surveillance and the basal extravasation of monocytes and lymphocytes into the sub-endothelial space [11]. The recent identification of selective antagonist compounds [36][37][38] will aid in our understanding of CXCR4 and SDF-1 function in the pathophysiology of vascular disease.…”

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.…”