A Small Molecule CXCR4 Inhibitor that Blocks T Cell Line–tropic HIV-1 Infection

Murakami, Tsutomu; Nakajima, Takeshi; Koyanagi, Yoshio; Tachibana, Kazunobu; Fujii, Nobutaka; Tamamura, Hirokazu; Yoshida, Nobuaki; Waki, Michinori; Matsumoto, Aki; Yoshie, Osamu; Kishimoto, Tadamitsu; Yamamoto, Naoki; Nagasawa, Takashi

doi:10.1084/jem.186.8.1389

Cited by 363 publications

(251 citation statements)

References 23 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Gupta

Pillarisetti

Lysko

1999

Journal of Leukocyte Biology

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Section: Discussionmentioning

confidence: 99%

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

Gupta

Pillarisetti

Lysko

1999

Journal of Leukocyte Biology

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2004

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RNA interference (RNAi) is an evolutionarily conserved process by which plants and animals protect their genomes utilizing small, double-stranded RNAs to degrade target RNAs in a sequence-specific manner. Post-transcriptional gene silencing by these moieties can lead to degradation of both cellular and viral RNAs. It has recently been shown that double-stranded, small interfering RNAs (siRNAs) of 21-25 nucleotides can be transfected into relevant cells to target specific RNAs. This approach was utilized to inhibit human immunodeficiency virus type I (HIV-1) infection in human cells. siRNAs with homology to a motif in the mRNA that encodes for the HIV-1 chemokine coreceptor CXCR4 was utilized. Complementary studies via immunofluorescence microscopy and fluorescence-activated cell sorting demonstrated downregulation of CXCR4 from the surface of cells transfected with the specific siRNAs. As well, siRNAs without sequence homology to CXCR4 were used as controls and demonstrated no downregulation of CXCR4. siRNAs targeted to another chemokine coreceptor, APJ, showed specificity for downregulation of APJ but had no effects on CXCR4.Transfections with siRNAs targeting CXCR4 mRNA were shown to inhibit HIV-1 envelope fusion, which is relatively resistant to most viral inhibitors targeting chemokine coreceptors. The specificity of this effect was demonstrated by the inhibition of fusion by CXCR4-tropic and dual-tropic (CXCR4 and CCR5) envelope glycoproteins from HIV-1 on CXCR4+ indicator cells, but the lack of effects by siRNAs targeting CXCR4 mRNA on dual-tropic HIV-1 envelopes in CCR5+ indicator cells utilizing these fusion assays. Interestingly, siRNAs targeting CXCR4 selectively inhibited CXCR4-tropic cell-free virus infection of human cells but at only modest levels as compared to cell:cell fusion. siRNA may be a potential molecular therapeutic approach to alter a cellular cofactor critical for infection of human cells by relevant strains of HIV-1. The targeting of a cellular cofactor, rather than the HIV-1-specific mRNAs or genomic RNA, holds promise as the rapid mutational ability of the HIV-1 genome may obviate the potential clinical use of RNAi directly against this virus.

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Schroers

et al. 2002

Gene Ther

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Intrakines, modified intracellular chemokines, offer a novel strategy to prevent cellular entry of HIV-1 by blocking the surface expression of HIV-1 co-receptors. To investigate potential clinical applications of the RANTES-intrakine, we explored the use of HIV-1-based lentiviral vectors for therapeutic gene transfer into T-lymphocytes. RANTES-intrakine genes can be efficiently transduced into primary human Tlymphocytes by lentiviral vectors, especially when human Tlymphocytes were stimulated with CD3 and CD28 antibodies. The transduced T cells showed decreased surface expression of the chemokine receptor CCR-5, as well as CCR-1 and CCR-3. This lentivirus-mediated approach to

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A Small Molecule CXCR4 Inhibitor that Blocks T Cell Line–tropic HIV-1 Infection

Cited by 363 publications

References 23 publications

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

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

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

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

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