Document Detail


Human glutaredoxin-1 catalyzes the reduction of HIV-1 gp120 and CD4 disulfides and its inhibition reduces HIV-1 replication.
MedLine Citation:
PMID:  19038358     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Reduction of intramolecular disulfides in the HIV-1 envelope protein gp120 occurs after its binding to the CD4 receptor. Protein disulfide isomerase (PDI) catalyzes the disulfide reduction in vitro and inhibition of this enzyme blocks viral entry. PDI belongs to the thioredoxin protein superfamily that also includes human glutaredoxin-1 (Grx1). Grx1 is secreted from cells and the protein has also been found within the HIV-1 virion. We show that Grx1 efficiently catalyzes gp120, and CD4 disulfide reduction in vitro, even at low plasma levels of glutathione. Grx1 catalyzes the reduction of two disulfide bridges in gp120 in a similar manner as PDI. Purified anti-Grx1 antibodies were shown to inhibit the Grx1 activity in vitro and block HIV-1 replication in cultured peripheral blood mononuclear cells. Also, the polyanion PRO2000, that was previously shown to prevent HIV entry, inhibits the Grx1- and PDI-dependent reduction of gp120 disulfides. Our findings suggest that Grx1 activity is important for HIV-1 entry and that Grx1 and the gp120 intramolecular disulfides are novel pharmacological targets for rational drug development.
Authors:
Joeri Auwerx; Ola Isacsson; Johan Söderlund; Jan Balzarini; Magnus Johansson; Mathias Lundberg
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-11-06
Journal Detail:
Title:  The international journal of biochemistry & cell biology     Volume:  41     ISSN:  1878-5875     ISO Abbreviation:  Int. J. Biochem. Cell Biol.     Publication Date:  2009 Jun 
Date Detail:
Created Date:  2009-02-23     Completed Date:  2009-10-26     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9508482     Medline TA:  Int J Biochem Cell Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1269-75     Citation Subset:  IM    
Affiliation:
Division of Clinical Microbiology, Karolinska University Hospital Huddinge, F68, Karolinska Institute, Stockholm, S-14186, Sweden.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD4 / metabolism*
Catalysis
Cattle
Disulfides / metabolism
Glutaredoxins / antagonists & inhibitors,  metabolism*,  pharmacology
Glutathione / metabolism
HIV Envelope Protein gp120 / metabolism*
HIV-1 / metabolism,  physiology*
Humans
Naphthalenesulfonates / pharmacology
Oxidation-Reduction
Polymers / pharmacology
Protein Disulfide-Isomerases / metabolism
Recombinant Proteins / pharmacology
Virus Internalization / drug effects
Virus Replication / drug effects,  physiology*
Chemical
Reg. No./Substance:
0/Antigens, CD4; 0/Disulfides; 0/Glutaredoxins; 0/HIV Envelope Protein gp120; 0/Naphthalenesulfonates; 0/PRO 2000; 0/Polymers; 0/Recombinant Proteins; 0/gp120 protein, Human immunodeficiency virus 1; 70-18-8/Glutathione; EC 5.3.4.1/Protein Disulfide-Isomerases

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