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Article: Mechanism of transdominant inhibition of CCR5-mediated HIV-1 infection by ccr5Δ32

TitleMechanism of transdominant inhibition of CCR5-mediated HIV-1 infection by ccr5Δ32
Authors
Issue Date1997
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
Citation
Journal Of Biological Chemistry, 1997, v. 272 n. 49, p. 30603-30606 How to Cite?
AbstractHuman chemokine receptor 5 (CCR5) functions as a co-receptor for Human immunodeficiency virus (HIV-1) infection. CCR5 is a seven-transmembrane cell surface receptor. Recently, a naturally occurring mutation of CCR5, ccr5Δ32, has been described. A small number of Caucasians are homozygously ccr5Δ32/ccr5Δ32, while a larger number of individuals are heterozygously CCR5/ccr5Δ32. The ccr5Δ32/ccr5Δ32 genotype has been linked to e phenotype that is 'highly' protected from HIV-1 infection. On the other hand, several studies have shown that the CCR5/ccr5Δ32 genotype confers 'relative' protection from AIDS with onset of disease being delayed by 2-4 years. Although it is known that peripheral blood lymphocytes from heterozygous individuals (CCR5/ccr5Δ32) support ex vivo HIV-1 replication at a reduced level compared with CCR5/CCR5 cells, the molecular basis for this observation is unknown. Here we report on events that post-translationally modify CCR5. We show that CCR5 progresses through the endoplasmic reticulum prior to appearing on the cell surface. Mature CCR5 can be post-translationally modified by phosphorylation and/or co-translationally by multimerization. By contrast, mutant ccr5Δ32, although retaining the capacity for multimerization, was incapable of being phosphorylated. ccr5Δ32 heterocomplexes with CCR5, and this interaction retains CCR5 in the endoplasmic reticulum resulting in reduced cell surface expression. Thus, co- expression in cells of ccr5Δ32 with CCR5 produces a trans-inhibition by the former of ability by the latter to support HIV-1 infection. Taken together, our findings suggest CCR5/ccr5Δ32 heterodimerization as a molecular explanation for the delayed onset of AIDS in CCR5/ccr5Δ32 individuals.
Persistent Identifierhttp://hdl.handle.net/10722/147411
ISSN
2015 Impact Factor: 4.258
2015 SCImago Journal Rankings: 3.151
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorBenkirane, Men_US
dc.contributor.authorJin, DYen_US
dc.contributor.authorChun, RFen_US
dc.contributor.authorKoup, RAen_US
dc.contributor.authorJeang, KTen_US
dc.date.accessioned2012-05-29T06:03:32Z-
dc.date.available2012-05-29T06:03:32Z-
dc.date.issued1997en_US
dc.identifier.citationJournal Of Biological Chemistry, 1997, v. 272 n. 49, p. 30603-30606en_US
dc.identifier.issn0021-9258en_US
dc.identifier.urihttp://hdl.handle.net/10722/147411-
dc.description.abstractHuman chemokine receptor 5 (CCR5) functions as a co-receptor for Human immunodeficiency virus (HIV-1) infection. CCR5 is a seven-transmembrane cell surface receptor. Recently, a naturally occurring mutation of CCR5, ccr5Δ32, has been described. A small number of Caucasians are homozygously ccr5Δ32/ccr5Δ32, while a larger number of individuals are heterozygously CCR5/ccr5Δ32. The ccr5Δ32/ccr5Δ32 genotype has been linked to e phenotype that is 'highly' protected from HIV-1 infection. On the other hand, several studies have shown that the CCR5/ccr5Δ32 genotype confers 'relative' protection from AIDS with onset of disease being delayed by 2-4 years. Although it is known that peripheral blood lymphocytes from heterozygous individuals (CCR5/ccr5Δ32) support ex vivo HIV-1 replication at a reduced level compared with CCR5/CCR5 cells, the molecular basis for this observation is unknown. Here we report on events that post-translationally modify CCR5. We show that CCR5 progresses through the endoplasmic reticulum prior to appearing on the cell surface. Mature CCR5 can be post-translationally modified by phosphorylation and/or co-translationally by multimerization. By contrast, mutant ccr5Δ32, although retaining the capacity for multimerization, was incapable of being phosphorylated. ccr5Δ32 heterocomplexes with CCR5, and this interaction retains CCR5 in the endoplasmic reticulum resulting in reduced cell surface expression. Thus, co- expression in cells of ccr5Δ32 with CCR5 produces a trans-inhibition by the former of ability by the latter to support HIV-1 infection. Taken together, our findings suggest CCR5/ccr5Δ32 heterodimerization as a molecular explanation for the delayed onset of AIDS in CCR5/ccr5Δ32 individuals.en_US
dc.languageengen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/en_US
dc.relation.ispartofJournal of Biological Chemistryen_US
dc.subject.meshChemokine Ccl4en_US
dc.subject.meshDisease Progressionen_US
dc.subject.meshGenotypeen_US
dc.subject.meshHiv Infections - Immunologyen_US
dc.subject.meshHiv-1en_US
dc.subject.meshHela Cellsen_US
dc.subject.meshHumansen_US
dc.subject.meshImmunity, Innateen_US
dc.subject.meshMacrophage Inflammatory Proteins - Metabolismen_US
dc.subject.meshMutationen_US
dc.subject.meshPhosphorylationen_US
dc.subject.meshProtein Processing, Post-Translationalen_US
dc.subject.meshReceptors, Ccr5 - Genetics - Physiologyen_US
dc.subject.meshSaccharomyces Cerevisiaeen_US
dc.titleMechanism of transdominant inhibition of CCR5-mediated HIV-1 infection by ccr5Δ32en_US
dc.typeArticleen_US
dc.identifier.emailJin, DY:dyjin@hkucc.hku.hken_US
dc.identifier.authorityJin, DY=rp00452en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1074/jbc.272.49.30603en_US
dc.identifier.pmid9388191-
dc.identifier.scopuseid_2-s2.0-0030712312en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0030712312&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume272en_US
dc.identifier.issue49en_US
dc.identifier.spage30603en_US
dc.identifier.epage30606en_US
dc.identifier.isiWOS:000071640800004-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridBenkirane, M=7004581121en_US
dc.identifier.scopusauthoridJin, DY=7201973614en_US
dc.identifier.scopusauthoridChun, RF=7005563719en_US
dc.identifier.scopusauthoridKoup, RA=7006766528en_US
dc.identifier.scopusauthoridJeang, KT=7004824803en_US
dc.identifier.citeulike2871184-

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