Human glutaredoxin-1 catalyzes the reduction of HIV-1 gp120 and CD4 disulfides and its inhibition reduces HIV-1 replication.
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.
Auwerx
Joeri
J
Division of Clinical Microbiology, Karolinska University Hospital Huddinge, F68, Karolinska Institute, Stockholm, S-14186, Sweden.
Isacsson
Ola
O
Söderlund
Johan
J
Balzarini
Jan
J
Johansson
Magnus
M
Lundberg
Mathias
M
D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism*; D002384:Catalysis; D002417:Cattle; D004220:Disulfides / Q000378:metabolism; D054477:Glutaredoxins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D009282:Naphthalenesulfonates / Q000494:pharmacology; D010084:Oxidation-Reduction; D011108:Polymers / Q000494:pharmacology; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D053586:Virus Internalization / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*
D015704:CD4 Antigens; D004220:Disulfides; D054477:Glutaredoxins; D015699:HIV Envelope Protein gp120; D009282:Naphthalenesulfonates; C120231:PRO 2000; D011108:Polymers; D011994:Recombinant Proteins; C514793:gp120 protein, Human immunodeficiency virus 1; D019704:Protein Disulfide-Isomerases; D005978:Glutathione