Role of the Amino-Terminal Extracellular Domain of CXCR-4 in Human Immunodeficiency Virus Type 1 Entry

Picard, Laurent; Wilkinson, David; McKnight, Áine; Gray, Patrick W.; Hoxie, James A.; Clapham, Paul R.; Weiss, Robin A.

doi:10.1006/viro.1997.8506

Cited by 88 publications

(98 citation statements)

References 53 publications

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“…They argued, however, that non-N-linked-glycosylated CXCR4 mediated R5 HIV-1 entry much less efficiently (100-1000-fold) in comparison to X4 HIV-1. Furthermore, other groups could not detect any alteration in entry of X4 [142,149,150], X4R5 [149] or R5 HIV-1 [150] isolates upon analysis of various CXCR4 mutants with replaced Nlinked glycosylation sites, although Thordsen et al also observed a slight increase in X4R5 infection under these conditions [150]. The apparent discrepancy of these findings might be partly explained by the experimental settings (cells, HIV isolates, infection assays, antibodies used for CXCR4 detection) as well as by the CXCR4 mutants tested (single N 11 versus double N 11 /N 176 substitutions and the type of residue replacing the N residue, such as Q, I or A) [146].…”

Section: Impact Of Change In Receptor Outlook By Glycosylation and Sumentioning

confidence: 90%

“…Out of the 2 potential N-glycosylation sites, only N 11 was concluded to be efficiently glycosylated, whereas the likely unglycosylated N 176 residue might support the three-dimensional structure of CXCR4 [144][145][146][147]. In the absence of Nglycans, the expression levels of CXCR4 remained mostly unaffected [142,[146][147][148][149][150], besides some minor increases [146] or decreases [144,149,150] which might be partly accountable to the detection efficiency of conformation-specific antibodies [135,142,151]. Notably, combined replacement of both potential N-linked glycosylation sites (N 11 Q/N 176 D) of CXCR4 led to the complete disruption of the epitope for the routinely used 12G5 monoclonal anti-CXCR4 antibody [142].…”

Section: Impact Of Change In Receptor Outlook By Glycosylation and Sumentioning

confidence: 99%

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Chemokine receptor internalization and intracellular trafficking

Neel

Schutyser

Sai

et al. 2005

Cytokine & Growth Factor Reviews

203

218

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The internalization and intracellular trafficking of chemokine receptors have important implications for the cellular responses elicited by chemokine receptors. The major pathway by which chemokine receptors internalize is the clathrin-mediated pathway, but some receptors may utilize lipid rafts/ caveolae-dependent internalization routes. This review discusses the current knowledge and controversies regarding these two different routes of endocytosis. The functional consequences of internalization and the regulation of chemokine receptor recycling will also be addressed. Modifications of chemokine receptors, such as palmitoylation, ubiquitination, glycosylation, and sulfation, may also impact trafficking, chemotaxis and signaling. Finally, this review will cover the internalization and trafficking of viral and decoy chemokine receptors.

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Section: Impact Of Change In Receptor Outlook By Glycosylation and Sumentioning

confidence: 90%

Section: Impact Of Change In Receptor Outlook By Glycosylation and Sumentioning

confidence: 99%

Chemokine receptor internalization and intracellular trafficking

Neel

Schutyser

Sai

et al. 2005

Cytokine & Growth Factor Reviews

203

218

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“…The NH 2 terminus was the first domain proposed to play a role in coreceptor function from studies showing NH 2 -terminal reactive polyclonal antibody blocking of fusion and virus entry (35). A second report demonstrated that the NH 2 terminus was indeed critical for some isolates yet not the sole element deemed important (52), while additional studies highlighted the importance of other domains, primarily ecl-2, in coreceptor activity (53,54). We have recently shown an importance of negatively charged glutamic acid residues in the NH 2 terminus, as well as some additional charged residues in the extracellular loops, for X4 Env coreceptor activity (12).…”

Section: Charge Introduction Into Ecl-2 and The Impairment Of Ccr5mentioning

confidence: 99%

Substitutions in a Homologous Region of Extracellular Loop 2 of CXCR4 and CCR5 Alter Coreceptor Activities for HIV-1 Membrane Fusion and Virus Entry

Chabot

Broder

2000

Journal of Biological Chemistry

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CXCR4 and CCR5 are the principal coreceptors for human immunodeficiency virus type-1 (HIV-1) infection. Previously, mutagenesis of CXCR4 identified single amino acid changes that either impaired CXCR4's coreceptor activity for CXCR4-dependent (X4) isolate envelope glycoproteins (Env) or expanded its activity, allowing it to serve as a functional coreceptor for CCR5-dependent (R5) isolates. The most potent of these point mutations was an alanine substitution for the aspartic acid residue at position 187 in extracellular loop 2 (ecl-2), and here we show that this mutation also permits a variety of primary R5 isolate Envs, including those of other subtypes (clades), to employ it as a coreceptor. We also examined the corresponding region of CCR5 and demonstrate that the substitution of the serine residue in the homologous ecl-2 position with aspartic acid impairs CCR5 coreceptor activity for isolates across several clades. These results highlight a homologous and critical element in ecl-2, of both the CXCR4 and CCR5 molecules, for their respective coreceptor activities. Charge elimination expands CXCR4 coreceptor activity, while a similar charge introduction can destroy the coreceptor function of CCR5. These findings provide further evidence that there are conserved elements in both CXCR4 and CCR5 involved in coreceptor function.Seven-transmembrane domain coreceptor molecules are required along with CD4 for human immunodeficiency virus type-1 (HIV-1) 1 envelope glycoprotein (Env)-mediated membrane fusion and virus entry (reviewed in Refs. 1-4). These coreceptors belong or are related to the chemokine receptor subfamily of the seven-transmembrane domain G-protein-coupled receptor superfamily (5). Although more than a dozen related coreceptor molecules have been shown by one or more laboratories to function in the fusion or entry of at least one virus isolate, it is now well recognized that the principal HIV-1 coreceptors remain the initially discovered CXC chemokine receptor CXCR4 and the CC-chemokine receptor CCR5 (6). The viral entry process is believed to occur through a receptormediated activation of Env's membrane fusogenic activity. The most favored model for the mechanism underlying this activation process involves at least two stages of receptor-induced conformational alterations in Env; the first is through CD4 binding, leading to exposure of the coreceptor binding site, followed by coreceptor binding and a further presumed conformational change resulting in the exposure and insertion of the hydrophobic fusion peptide domain of the gp41 NH 2 terminus into the receptor-bearing target cell (reviewed in detail in Refs. 7 and 8). Defining the elements of the coreceptor molecules involved in Env interaction and the membrane fusion process remains an area of critical importance for our complete understanding of the virus entry mechanism. To date, a variety of studies, employing the use of both Env and coreceptor genetic chimeras and mutations, have provided an extensive array of important structural information on...

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“…The mechanism of this inhibition is not yet known but most probably involves steric blockade of the co-receptor by the ligand. Alternatively, chemokine-mediated inhibition of HIV entry may be due to downregulation of the receptor on the surface of permissive cells (17).…”

mentioning

confidence: 99%

CCR5 genotype and plasma ß-chemokine concentration of Brazilian HIV-infected individuals

Mikawa

Tagliavini

Costa

2002

Braz J Med Biol Res

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The 32-bp deletion in the HIV-1 co-receptor CCR5 confers a high degree of resistance to HIV-1 infection in homozygous individuals for the deleted allele and partial protection against HIV-1 during disease progression in heterozygotes. Natural ligands for CCR5, MIP-1a, MIP-1ß and RANTES, have been shown to inhibit HIV replication in CD4+ T cells. In the present study, we examined the CCR5 genotype by PCR and the plasma levels of RANTES and MIP-1a by ELISA among blood donors (N = 26) and among HIV-1-infected individuals (N = 129). The control group consisted of healthy adult volunteers and HIV-1-infected subjects were an asymptomatic and heterogeneous group of individuals with regard to immunologic and virologic markers of HIV-1 disease. The frequency of the CCR5 mutant allele (D32ccr5) in this population was 0.032; however, no D32ccr5 homozygote was detected. These results could be related to the intense ethnic admixture of the Brazilian population. There was no correlation between circulating ß-chemokines (MIP-1a, RANTES) and viral load in HIV-infected individuals. RANTES concentrations in plasma samples from HIV+ patients carrying the homozygous CCR5 allele (CCR5/CCR5) (28.23 ng/ml) were higher than in the control samples (16.07 ng/ml; P<0.05); however, this HIV+ patient group (mean 26.23 pg/ml) had significantly lower concentrations of MIP-1a than those observed in control samples (mean 31.20 pg/ml; P<0.05). Both HIV-1-infected and uninfected individuals heterozygous for the D32ccr5 allele had significantly lower concentrations of circulating RANTES (mean 16.07 and 6.11 ng/ml, respectively) than CCR5/CCR5 individuals (mean 28.23 and 16.07 ng/ml, respectively; P<0.05). These findings suggest that the CCR5 allele and ß-chemokine production may affect the immunopathogenesis of HIV-1.

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Role of the Amino-Terminal Extracellular Domain of CXCR-4 in Human Immunodeficiency Virus Type 1 Entry

Cited by 88 publications

References 53 publications

Chemokine receptor internalization and intracellular trafficking

Chemokine receptor internalization and intracellular trafficking

Substitutions in a Homologous Region of Extracellular Loop 2 of CXCR4 and CCR5 Alter Coreceptor Activities for HIV-1 Membrane Fusion and Virus Entry

CCR5 genotype and plasma ß-chemokine concentration of Brazilian HIV-infected individuals

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