Discovery of a Natural Defense Against HIV With Therapeutic Potential

The first step in the HIV entry process into the host cell is initiated by the binding of the HIV envelope (Env) glycoprotein gp120 to the CD4+ T-cell receptor and the CCR5/CXCR4 coreceptors on the target cell surface. The three-dimensional functional structure of gp120 contains intramolecular disulfide bonds, which are critical for the interaction with the CD4 receptor. Env is folded into this conformation in the endoplasmic reticulum (ER) and delivered to the cell surface. However, the efficiency of HIV-1 Env folding is very low; indeed, almost 85% of Env proteins are retained in the ER and degraded. Although the degradation mechanism is unclear, it has been demonstrated that HIV-1 Env is targeted to the ER-associated protein degradation pathway for clearance.