The gene HFE, which when mutated may cause the systemic iron overload disorder hereditary hemochromatosis, influences HIV-mediated iron dysregulation: the HFE gene product normally competes with transferrin for binding to the transferrin receptor (TFR), reducing its affinity for iron-bound transferrin and lowering macrophage iron content, but HIV Nef downregulates the expression of wildtype HFE protein on the cell surface, counteracting these effects and leading to elevated systemic indices of iron (e. g., serum ferritin and/or transferrin saturation) [27]. Here, TF is linked to hereditary hemochromatosis.