A Dual-Tropic Primary HIV-1 Isolate That Uses Fusin and the β-Chemokine Receptors CKR-5, CKR-3, and CKR-2b as Fusion Cofactors

Doranz, Benjamin J.; Rucker, Joseph; Yi, Yanjie; Smyth, Robert J.; Samson, Michel; Peiper, Stephen C.; Parmentier, Marc; Collman, Ronald G.; Doms, Robert W.

doi:10.1016/s0092-8674(00)81314-8

Cited by 1,744 publications

(1,241 citation statements)

References 53 publications

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“…25,26 CXCR4 belongs to the family of seven transmembrane G-proteincoupled receptors. [27][28][29][30][31] These coreceptors transduce signals via heterotrimeric G-proteins. CXCR4 has been clearly identified as one of the major coreceptors for HIV-1 cell entry in vivo.…”

Section: Introductionmentioning

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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Section: Introductionmentioning

confidence: 99%

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

et al. 2004

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“…1,2 R5 (macrophage, M) tropic HIV-1 infects macrophages and primary CD4 + T cells mainly by using the CC-chemokine receptor 5 (CCR-5) as its principal co-receptor. [3][4][5][6][7][8] X4 (T cell line-tropic) HIV-1 strains infect CD4 + T cells primarily by using the co-receptor CXCR-4. Although other chemokine receptors can also participate in HIV-1 infection, CCR-5 has a critical role in both the initial infectious process and the progression of the disease.…”

Section: Introductionmentioning

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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“…gp120, which enables binding to a chemokine coreceptor either CCR5 (for R5 tropic cells) or CXCR4 (for X4 tropic cells). [13][14][15][16] Generally, HIV chemokine coreceptor selectivity is correlated to the overall positive charge of the V3 variable loop region on gp120, where low overall positive charge promotes CCR5 binding and high overall positive charge promotes CXCR4 binding. [17] After binding the chemokine coreceptor, a second conformational change in the gp120 trimer occurs leading to the exposure of the gp41 trimer in its prefusogenic state.…”

Section: Hiv Life Cyclementioning

confidence: 99%

Polymeric Anti‐HIV Therapeutics

Danial

Klok

2014

Macromolecular Bioscience

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The scope of this review is to highlight the application of polymer therapeutics in an effort to curb the transmission and infection of the human immunodeficiency virus (HIV). Following a description of the HIV life cycle, the use of approved antiretroviral drugs that inhibit critical steps in the HIV infection process is highlighted. After that, a comprehensive overview of the structure and inhibitory properties of polymeric anti‐HIV therapeutic agents is presented. This overview will include inhibitors based on polysaccharides, synthetic polymers, dendritic polymers, polymer conjugates as well as polymeric DC‐SIGN antagonists. The review will conclude with a section that discusses the applications of polymers and polymer conjugates as systemic and topical anti‐HIV therapeutics.

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A Dual-Tropic Primary HIV-1 Isolate That Uses Fusin and the β-Chemokine Receptors CKR-5, CKR-3, and CKR-2b as Fusion Cofactors

Cited by 1,744 publications

References 53 publications

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

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

Polymeric Anti‐HIV Therapeutics

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