Small molecule inhibitor of HIV-1 cell fusion blocks chemokine receptor-mediated function

Howard, O. M. Zack; Korte, Thomas; Tarasova, Nadya I.; Grimm, Michael; Turpin, Jim A.; Rice, William G.; Michejda, Christopher J.; Blumenthal, Robert; Oppenheim, Joost J.

doi:10.1002/jlb.64.1.6

Cited by 49 publications

(35 citation statements)

References 31 publications

(48 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Targeting chemokine receptors to block HIV infection is beginning to show promise as an effective means to control viremia in infected individuals. [8][9][10][11] "Lipid rafts" is a broad term for the collection of membrane microdomains enriched in cholesterol, sphingolipids, glycosylphosphatidylinositol-anchored proteins, and acylated signaling molecules. 12 Lipid rafts are believed to be important signaling platforms enriched in many signaling proteins, including but not limited to src kinases, G␣ subunit, H-Ras, linker for activation of T cells (LAT), and nitric oxide synthase (NOS).…”

Section: Introductionmentioning

confidence: 99%

Cholesterol is essential for macrophage inflammatory protein 1β binding and conformational integrity of CC chemokine receptor 5

Nguyen

Taub

2002

Blood

122

100

View full text Add to dashboard Cite

The chemokine receptor, CCR5, is used as a human immunodeficiency virus coreceptor in combination with CD4 during transmission and early infection. CCR5 has been shown to be palmitoylated and targeted to cholesterol-and sphingolipidrich membrane microdomains termed "lipid rafts." However, the role of cholesterol and lipid rafts on chemokine binding and signaling through CCR5 remains unknown. We found that cholesterol extraction by hydroxypropyl-␤-cyclodextrin (

show abstract

Section: Introductionmentioning

confidence: 99%

Cholesterol is essential for macrophage inflammatory protein 1β binding and conformational integrity of CC chemokine receptor 5

Nguyen

Taub

2002

Blood

122

100

View full text Add to dashboard Cite

show abstract

“…Since NSC 651016 is known to interfere with HIV replication after CD4-gp120 and before viral pore formation, 40 these observations suggest that R223Q may alter the position of CCR5 domains involved in viral pore formation. The exact CCR5 domains involved in gp41-mediated fusion have not been fully characterized, but modeling studies suggest that extracellular loop 2 and TM domain 5 may participate based on molecular models of the TAK-779 inhibitor interacting with CCR5 and epitope mapping studies.…”

Section: Discussionmentioning

confidence: 93%

“…by adding CCL5 or the fusion inhibitor NSC 651016 40 to the culture. Since NSC 651016 is known to interfere with HIV replication after CD4-gp120 and before viral pore formation, 40 these observations suggest that R223Q may alter the position of CCR5 domains involved in viral pore formation.…”

Section: Discussionmentioning

confidence: 99%

“…40 Following electroporation, cells were cultured for 24 h without geneticin followed by removal of the nonadherent cells. The adherent cells were counted and plated at a density of 1 Â 10 5 cells/well in a 24-well plate for overnight culture.…”

Section: Hiv-1 Infection Of Hek-ccr5 Variant Transfectantsmentioning

confidence: 99%

“…To determine the effects of these variants, we have studied their ability to support live HIV-1 infection, ligand blockade of HIV-1 infection and the function of a fusion inhibitor (NSC 651016 (2,2 0 amino]bis[N, 4 0 -di[pyrrole-2-carboxamide-1,1 0 -dimethyl] ]-6,8 napthalenedisulfonic acid]hexasodium salt)). 40 The effect of these genetic variants on chemokine binding, chemokine-induced cell migration and calcium mobilization was also determined.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Variants of CCR5, which are permissive for HIV-1 infection, show distinct functional responses to CCL3, CCL4 and CCL5

et al. 2005

View full text Add to dashboard Cite

CCR5 is one of the primary coreceptors for Env-mediated fusion between cells and human immunodeficiency virus type 1 (HIV-1). Analyses of CCR5 variants in cohorts of HIV-1 high-risk individuals led to the identification of multiple single amino-acid substitutions, which may have functional consequences. This study focused on eight naturally occurring allelic variants located between amino-acid residues 60 and 334 of CCR5. All studied allelic variants were highly expressed on the cell surface of HEK-293 cells and permissive for HIV-1 infection. Variant G301V showed 3.5-fold increase in 50% effective concentration (EC 50 ) for CCL4 (MIP 1beta) in a competitive binding assay. There was also a significant reduction in CCL5 (RANTES) EC 50 for the R223Q, A335V and Y339F variants. The most unexpected functional abnormality was exhibited by the R60S variant that exhibited a loss of ligand-induced desensitization in chemotaxis assays, but showed normal CCL4 and CCL5 binding avidity. This mutation is located in the first intracellular loop, a domain that has not previously been shown to be involved in receptor desensitization. In conclusion, our results support earlier studies showing that these naturally occurring point mutations do not limit HIV-1 infection, and indicated that single amino-acid changes can have unexpected functional consequences.

show abstract

Current Evidence and Future Directions for Targeting HIV Entry

Mp¹,

Cairns²,

Sf³

2000

JAMA

View full text Add to dashboard Cite

Great strides have been made in developing potent antiretroviral regimens that block human immunodeficiency virus (HIV) transcription and assembly. Despite these therapeutic advances, problems of drug resistance, latent viral reservoirs, and drug-induced toxic effects that compromise effective viral control point to the need for new classes of anti-HIV drugs with different modes of action. One promising approach involves blocking HIV entry into human cells, a complex process that involves multiple protein interactions. The process of HIV entry begins with binding of the viral envelope glycoprotein to both the CD4 receptor and one of several chemokine receptors and ends with fusion of viral and cell membranes. Conceptually, there are 3 steps in the HIV entry process that could serve as therapeutic targets: binding of the viral envelope glycoprotein with the CD4 receptor, binding of the envelope-CD4 complex to chemokine receptors, and fusion of the viral and cell membranes. Preclinical and clinical assessment of these entry inhibitors is ongoing and will determine if they possess properties required for drug licensure. Moreover, the worldwide epidemic is largely occurring in developing countries that cannot afford these drugs: a prophylactic vaccine is necessary and urgent. New knowledge of the HIV-envelope glycoprotein has also provided insight into possibilities for the design of novel HIV vaccines. JAMA. 2000;284:215-222

show abstract

Small molecule inhibitor of HIV-1 cell fusion blocks chemokine receptor-mediated function

Cited by 49 publications

References 31 publications

Cholesterol is essential for macrophage inflammatory protein 1β binding and conformational integrity of CC chemokine receptor 5

Cholesterol is essential for macrophage inflammatory protein 1β binding and conformational integrity of CC chemokine receptor 5

Variants of CCR5, which are permissive for HIV-1 infection, show distinct functional responses to CCL3, CCL4 and CCL5

Current Evidence and Future Directions for Targeting HIV Entry

Contact Info

Product

Resources

About