| http://purl.uniprot.org/citations/17686153 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/17686153 | http://www.w3.org/2000/01/rdf-schema#comment | "BackgroundHIV-1 envelope glycoprotein (Env) induces membrane fusion as a result of sequential binding to CD4 and chemokine receptors (CCR5 or CXCR4). The critical determinants of CCR5 coreceptor function are the N-terminal domain (Nt) and the second extracellular loop. However, mutations in gp120 adapt HIV-1 to grow on cells expressing the N-terminally truncated CCR5(Delta 18) (Platt et al., J. Virol. 2005, 79: 4357-68).ResultsWe have functionally characterized the adapted Env (designated Env(NYP)) using a quantitative cell-cell fusion assay. The rate of fusion with target cells expressing wild-type CCR5 and the resistance to fusion inhibitors was virtually identical for wild-type Env and Env(NYP), implying that the coreceptor affinity had not increased as a result of adaptation. In contrast, Env(NYP)-induced fusion with cells expressing CCR5(Delta 18) occurred at a slower rate and was extremely sensitive to the CCR5 binding inhibitor, Sch-C. Resistance to Sch-C drastically increased after pre-incubation of Env(NYP)- and CCR5(Delta 18)-expressing cells at a temperature that was not permissive to fusion. This indicates that ternary Env(NYP)-CD4-CCR5(Delta 18) complexes accumulate at sub-threshold temperature and that low-affinity interactions with the truncated coreceptor are sufficient for triggering conformational changes in the gp41 of Env(NYP) but not in wild-type Env. We also demonstrated that the ability of CCR5(Delta 18) to support fusion and infection mediated by wild-type Env can be partially reconstituted in the presence of a synthetic sulfated peptide corresponding to the CCR5 Nt. Pre-incubation of wild-type Env- and CCR5(Delta 18)-expressing cells with the sulfated peptide at sub-threshold temperature markedly increased the efficiency of fusion.ConclusionWe propose that, upon binding the Nt region of CCR5, wild-type Env acquires the ability to productively engage the extracellular loop(s) of CCR5 - an event that triggers gp41 refolding and membrane merger. The adaptive mutations in Env(NYP) enable it to more readily release its hold on gp41, even when it interacts weakly with a severely damaged coreceptor in the absence of the sulfopeptide."xsd:string |
| http://purl.uniprot.org/citations/17686153 | http://purl.org/dc/terms/identifier | "doi:10.1186/1742-4690-4-55"xsd:string |
| http://purl.uniprot.org/citations/17686153 | http://purl.uniprot.org/core/author | "Kabat D."xsd:string |
| http://purl.uniprot.org/citations/17686153 | http://purl.uniprot.org/core/author | "Melikyan G.B."xsd:string |
| http://purl.uniprot.org/citations/17686153 | http://purl.uniprot.org/core/author | "Platt E.J."xsd:string |
| http://purl.uniprot.org/citations/17686153 | http://purl.uniprot.org/core/date | "2007"xsd:gYear |
| http://purl.uniprot.org/citations/17686153 | http://purl.uniprot.org/core/name | "Retrovirology"xsd:string |
| http://purl.uniprot.org/citations/17686153 | http://purl.uniprot.org/core/pages | "55"xsd:string |
| http://purl.uniprot.org/citations/17686153 | http://purl.uniprot.org/core/title | "The role of the N-terminal segment of CCR5 in HIV-1 Env-mediated membrane fusion and the mechanism of virus adaptation to CCR5 lacking this segment."xsd:string |
| http://purl.uniprot.org/citations/17686153 | http://purl.uniprot.org/core/volume | "4"xsd:string |
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| http://purl.uniprot.org/uniprot/#_A0A089G7G7-mappedCitation-17686153 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/17686153 |
| http://purl.uniprot.org/uniprot/#_A0A089G7G9-mappedCitation-17686153 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/17686153 |
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| http://purl.uniprot.org/uniprot/#_A0A089G5M8-mappedCitation-17686153 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/17686153 |
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