Disulfide exchange in domain 2 of CD4 is required for entry of HIV-1.
CD4, a member of the immunoglobulin superfamily of receptors that mediates cell-cell interactions in the immune system, is the primary receptor for HIV-1. The extracellular portion of CD4 is a concatenation of four immunoglobulin-like domains, D1 to D4. The D1, D2 and D4 domains each contain a disulfide bond. We show here that the D2 disulfide bond is redox-active. The redox state of the thiols (disulfide versus dithiol) appeared to be regulated by thioredoxin, which is secreted by CD4(+) T cells. Locking the CD4 and the thioredoxin active-site dithiols in the reduced state with a hydrophilic trivalent arsenical blocked entry of HIV-1 into susceptible cells. These findings indicate that redox changes in CD4 D2 are important for HIV-1 entry and represent a new target for HIV-1 entry inhibitors.
Matthias
Lisa J
LJ
Centre for Thrombosis and Vascular Research, School of Medical Sciences, University of New South Wales and Department of Haematology, Prince of Wales Hospital, Sydney, NSW 2052, Australia.
Yam
Patricia T W
PT
Jiang
Xing-Mai
XM
Vandegraaff
Nick
N
Li
Peng
P
Poumbourios
Pantelis
P
Donoghue
Neil
N
Hogg
Philip J
PJ
D001152:Arsenicals / Q000737:chemistry; D001710:Biotin / Q000031:analogs & derivatives* / Q000737:chemistry; D015704:CD4 Antigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003545:Cysteine / Q000235:genetics; D005978:Glutathione / Q000031:analogs & derivatives* / Q000737:chemistry; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D015151:Immunoblotting; D008239:Lysine / Q000031:analogs & derivatives / Q000737:chemistry; D008301:Maleimides / Q000737:chemistry; D009154:Mutation; D010084:Oxidation-Reduction; D017434:Protein Structure, Tertiary; D015728:Receptors, HIV / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D013388:Succinimides / Q000737:chemistry; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D013879:Thioredoxins / Q000276:immunology / Q000378:metabolism
C426645:4-(N-(S-glutathionylacetyl)amino)phenylarsenoxide; D001152:Arsenicals; D015704:CD4 Antigens; D008301:Maleimides; D015728:Receptors, HIV; D013388:Succinimides; D013438:Sulfhydryl Compounds; C053827:biotinyl-N-hydroxysulfosuccinimide ester; D013879:Thioredoxins; D001710:Biotin; C047272:3-(N-maleimidopropionyl)biocytin; D005978:Glutathione; D008239:Lysine; D003545:Cysteine