CD4 mediates immune cell-cell interactions and is required for HIV to enter cells, but the precise nature of the molecular interactions involved has been unclear. In July 1 advanced online Nature Immunology, Lisa Matthias and colleagues at the University of New South Wales, Sydney, Australia, show that disulfide exchange in domain 2 of CD4 is required for entry of HIV-1 into susceptible cells (Nat Immunol 2002, DOI: 10.1038/ni815).

Matthias et al. observed that disulfide bonds exist in the reduced dithiol form on the cell surface of CD4⁺ T cells and that their redox state (disulfide versus dithiol) appears to be regulated by thioredoxin, a protein secreted by CD4⁺ cells. When they locked the CD4 and thioredoxin active-site dithiols in the reduced state (with a hydrophilic trivalent arsenical) HIV-1 could not enter previously susceptible CD4⁺ cells.

"Perturbation of this redox event may be a...