Document Detail


Site-specific mutations in HIV-1 gp41 reveal a correlation between HIV-1-mediated bystander apoptosis and fusion/hemifusion.
MedLine Citation:
PMID:  17416587     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Himanshu Garg; Anjali Joshi; Eric O Freed; Robert Blumenthal
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural     Date:  2007-04-06
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  282     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2007 Jun 
Date Detail:
Created Date:  2007-06-04     Completed Date:  2007-07-10     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  16899-906     Citation Subset:  IM    
Affiliation:
Membrane Structure and Function Section, Center for Cancer Research Nanobiology Program, NCI, National Institutes of Health, Frederick, Maryland 21702, USA.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis* / 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:
0/Cysteine Proteinase Inhibitors; 0/HIV Envelope Protein gp41; 0/Reverse Transcriptase Inhibitors; 159989-64-7/Nelfinavir; EC 3.4.22.-/Caspase 3

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