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Molecular mapping of epitopes for interaction of HIV-1 as well as natural ligands with the chemokine receptors, CCR5 and CXCR4.

Antonsson, Liselotte LU ; Boketoft, Åke LU ; Garzino-Demo, Alfredo; Olde, Björn LU and Owman, Christer LU (2003) In AIDS 17(18). p.2571-2579
Abstract
OBJECTIVE: Mapping coreceptor epitopes used by the prototypic R5 and X4 strains, HIV-1BaL and HIV-1IIIB, in comparison with epitopes involved in the activation and signaling induced by the natural ligands, RANTES and SDF-1beta. DESIGN: Receptor hybrids between CCR5 and CXCR4 were constructed. METHODS: Using single-overlap and extension PCR, increasing portions of CCR5 were replaced with corresponding parts of CXCR4. Viral interaction with these constructs was monitored in infection experiments using stably transfected cell lines, and ligand-induced activation of cells transiently expressing the constructs was measured in terms of calcium fluxes. RESULTS: SDF-1beta required an essentially complete CXCR4, whereas RANTES demanded both the N... (More)
OBJECTIVE: Mapping coreceptor epitopes used by the prototypic R5 and X4 strains, HIV-1BaL and HIV-1IIIB, in comparison with epitopes involved in the activation and signaling induced by the natural ligands, RANTES and SDF-1beta. DESIGN: Receptor hybrids between CCR5 and CXCR4 were constructed. METHODS: Using single-overlap and extension PCR, increasing portions of CCR5 were replaced with corresponding parts of CXCR4. Viral interaction with these constructs was monitored in infection experiments using stably transfected cell lines, and ligand-induced activation of cells transiently expressing the constructs was measured in terms of calcium fluxes. RESULTS: SDF-1beta required an essentially complete CXCR4, whereas RANTES demanded both the N terminus and the first two extracellular loops of CCR5. HIV-1 infection experiments emphasized the importance of the CCR5 N terminus for infection with HIV-1BaL, whereas HIV-1IIIB was less demanding in its use of CXCR4. CONCLUSION: This study, for the first time monitoring CCR5 and CXCR4 ligand activation and HIV-1 interaction concomitantly, indicates that ligands and virus use different receptor epitopes which, in turn, vary between the two receptors. One particular chimera (FC-4b), having its junctional region close to the conserved cysteine in ECL2, functioned as coreceptor for both HIV-1BaL and HIV-1IIIB, but was not activated with RANTES or SDF-1beta. The results provide a basis for tailoring drugs that block viral entry through the two major coreceptors without interfering with their physiological function. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
AIDS
volume
17
issue
18
pages
2571 - 2579
publisher
Lippincott Williams & Wilkins
external identifiers
  • wos:000220672800004
  • pmid:14685051
  • scopus:1642546647
ISSN
1473-5571
DOI
10.1097/01.aids.0000096906.73209.f0
language
English
LU publication?
yes
id
0c8b7615-560a-4920-8105-fcc839440f1f (old id 119517)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14685051&dopt=Abstract
date added to LUP
2007-07-10 09:32:46
date last changed
2018-01-07 05:47:00
@article{0c8b7615-560a-4920-8105-fcc839440f1f,
  abstract     = {OBJECTIVE: Mapping coreceptor epitopes used by the prototypic R5 and X4 strains, HIV-1BaL and HIV-1IIIB, in comparison with epitopes involved in the activation and signaling induced by the natural ligands, RANTES and SDF-1beta. DESIGN: Receptor hybrids between CCR5 and CXCR4 were constructed. METHODS: Using single-overlap and extension PCR, increasing portions of CCR5 were replaced with corresponding parts of CXCR4. Viral interaction with these constructs was monitored in infection experiments using stably transfected cell lines, and ligand-induced activation of cells transiently expressing the constructs was measured in terms of calcium fluxes. RESULTS: SDF-1beta required an essentially complete CXCR4, whereas RANTES demanded both the N terminus and the first two extracellular loops of CCR5. HIV-1 infection experiments emphasized the importance of the CCR5 N terminus for infection with HIV-1BaL, whereas HIV-1IIIB was less demanding in its use of CXCR4. CONCLUSION: This study, for the first time monitoring CCR5 and CXCR4 ligand activation and HIV-1 interaction concomitantly, indicates that ligands and virus use different receptor epitopes which, in turn, vary between the two receptors. One particular chimera (FC-4b), having its junctional region close to the conserved cysteine in ECL2, functioned as coreceptor for both HIV-1BaL and HIV-1IIIB, but was not activated with RANTES or SDF-1beta. The results provide a basis for tailoring drugs that block viral entry through the two major coreceptors without interfering with their physiological function.},
  author       = {Antonsson, Liselotte and Boketoft, Åke and Garzino-Demo, Alfredo and Olde, Björn and Owman, Christer},
  issn         = {1473-5571},
  language     = {eng},
  number       = {18},
  pages        = {2571--2579},
  publisher    = {Lippincott Williams & Wilkins},
  series       = {AIDS},
  title        = {Molecular mapping of epitopes for interaction of HIV-1 as well as natural ligands with the chemokine receptors, CCR5 and CXCR4.},
  url          = {http://dx.doi.org/10.1097/01.aids.0000096906.73209.f0},
  volume       = {17},
  year         = {2003},
}