Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Arsenicals / chemistry
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Biotin / analogs & derivatives*
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Biotin / chemistry
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CD4 Antigens / chemistry
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CD4 Antigens / immunology*
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CD4 Antigens / metabolism
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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Cysteine / genetics
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Glutathione / analogs & derivatives*
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Glutathione / chemistry
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HIV-1 / immunology*
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Humans
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Immunoblotting
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Lysine / analogs & derivatives
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Lysine / chemistry
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Maleimides / chemistry
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Mutation
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Oxidation-Reduction
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Protein Structure, Tertiary
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Receptors, HIV / chemistry
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Receptors, HIV / immunology*
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Receptors, HIV / metabolism
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Succinimides / chemistry
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Sulfhydryl Compounds / chemistry
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Sulfhydryl Compounds / immunology
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Sulfhydryl Compounds / metabolism
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Thioredoxins / immunology
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Thioredoxins / metabolism
Substances
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4-(N-(S-glutathionylacetyl)amino)phenylarsenoxide
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Arsenicals
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CD4 Antigens
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Maleimides
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Receptors, HIV
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Succinimides
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Sulfhydryl Compounds
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biotinyl-N-hydroxysulfosuccinimide ester
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Thioredoxins
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Biotin
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3-(N-maleimidopropionyl)biocytin
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Glutathione
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Lysine
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Cysteine