| Site-specific mutations in HIV-1 gp41 reveal a correlation between HIV-1-mediated bystander apoptosis and fusion/hemifusion. | |
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MedLine Citation:
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PMID: 17416587 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The loss of CD4(+) T cells in HIV-1 infections is hypothesized to be caused by apoptosis of bystander cells mediated by cell surface-expressed HIV-1 Env glycoprotein. However, the mechanism by which Env mediates this process remains controversial. Specifically, the role of HIV-1 gp120 binding to CD4 and CXCR4 versus the fusion process mediated by gp41 remains unresolved. Env-induced apoptosis in bystander cells has been shown to be gp41-dependent and correlates with the redistribution of membrane lipids between Env-expressing cells and target cells (hemifusion). Using a rational mutagenesis approach aimed at targeting Env function via the gp41 subunit, we examined the role of HIV gp41 in bystander apoptosis. A mutation in the fusion domain of gp41 (V513E) resulted in a fusion-defective Env that failed to induce apoptosis. A mutation in the gp41 N-terminal helix (G547D) reduced cell fusion capacity and apoptosis; conversely, an Env mutant with a deletion of the gp41 cytoplasmic tail (Ct Del) enhanced both cell-to-cell fusion and apoptosis. Most significantly, an Env mutant containing a substitution in the loop region of gp41 (D589L) mediated transfer of lipids (hemifusion) to bystander cells but was defective in cell-to-cell and to a lesser degree virus-to-cell fusion. This mutant was still able to induce apoptosis in bystander cells. Hence, we have provided the first direct evidence that gp41-mediated hemifusion is both required and sufficient for induction of apoptosis in bystander cells. These results may help to explain the mechanism of HIV-1 Env-induced T cell depletion. |
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Authors:
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Himanshu Garg; Anjali Joshi; Eric O Freed; Robert Blumenthal |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Intramural Date: 2007-04-06 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 282 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2007 Jun |
Date Detail:
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Created Date: 2007-06-04 Completed Date: 2007-07-10 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 16899-906 Citation Subset: IM |
Affiliation:
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Membrane Structure and Function Section, Center for Cancer Research Nanobiology Program, NCI, National Institutes of Health, Frederick, Maryland 21702, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis*
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drug effects Caspase 3 / antagonists & inhibitors Cysteine Proteinase Inhibitors / pharmacology HIV Envelope Protein gp41 / genetics, physiology* HIV-1 / physiology* Hela Cells Humans Membrane Fusion / physiology* Mutagenesis, Site-Directed Nelfinavir / pharmacology Reverse Transcriptase Inhibitors / pharmacology Virus Replication |
| Chemical | |
Reg. No./Substance:
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0/Cysteine Proteinase Inhibitors; 0/HIV Envelope Protein gp41; 0/Reverse Transcriptase Inhibitors; 159989-64-7/Nelfinavir; EC 3.4.22.-/Caspase 3 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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