Thioredoxin-1 and protein disulfide isomerase catalyze the reduction of similar disulfides in HIV gp120.
HIV-1 enters cells via interaction of the viral glycoprotein gp120, the host cell surface receptor CD4 and the co-receptors CCR5 or CXCR4. For entry, gp120 undergoes conformational changes that depend on the reduction of one or more disulfides. Previous studies indicate that protein disulfide isomerase (PDI), thioredoxin-1 (Trx1), and glutaredoxin-1 (Grx1) catalyze gp120 reduction, but their specific disulfide targets are not known. Here, it was demonstrated that PDI and Trx1 have similar gp120 disulfide targets as determined by labeling after reduction, but with some pattern differences, including overall stronger labeling with Trx1 than with PDI. Furthermore, uneven labeling of the residues of a disulfide may reflect altered accessibility by conformational changes upon the reduction process. Since both PDI and Trx1 may be involved in viral entry, compounds that target the host redox system or the viral gp120 were tested in vitro to investigate whether redox regulation is a target for anti-HIV therapy. Carbohydrate binding agents (CBAs), previously shown to bind gp120 and inhibit HIV entry, were now demonstrated to inhibit gp120 disulfide reduction. Auranofin, an inhibitor of thioredoxin reductase 1 (TrxR1), also showed inhibitory activity towards HIV infection, although close to its cytotoxic concentration. Our results demonstrate that both the host redox system and the viral surface glycoproteins are of interest for the development of new generations of anti-HIV therapeutics.
Department of Laboratory Medicine, Division of Clinical Microbiology, F68, Karolinska Institutet, SE-14186 Huddinge, Sweden.
Kathrin
K
Reiser
Katrien O
KO
François
Dominique
D
Schols
Tomas
T
Bergman
Hans
H
Jörnvall
Jan
J
Balzarini
Anna
A
Karlsson
Mathias
M
Lundberg
D000494:Allosteric Regulation; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001310:Auranofin / Q000494:pharmacology; D002417:Cattle; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism*; D015658:HIV Infections / Q000378:metabolism* / Q000503:physiopathology / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D013058:Mass Spectrometry; D010084:Oxidation-Reduction / Q000187:drug effects; D011487:Protein Conformation; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D051381:Rats; D013879:Thioredoxins / Q000378:metabolism*; D053586:Virus Internalization; D014779:Virus Replication
D000998:Antiviral Agents; D004220:Disulfides; D015699:HIV Envelope Protein gp120; D001310:Auranofin; D013879:Thioredoxins; D019704:Protein Disulfide-Isomerases