The Vpu protein acts in the degradation of CD4 in the endoplasmic reticulum and in the enhancement of virion release from the plasma membrane of infected cells.

Since then, Vpu has been shown to form cation-selective ion channels when expressed in Xenopus oocytes or mammalian cells and also when purified and reconstituted into planar lipid bilayers.

In the case of CD4, Vpu acts as a molecular adaptor to connect CD4 to an E3 ubiquitin ligase complex resulting in CD4 degradation by cellular proteasomes.

Enhancement of virus release on the other hand involves the neutralization of a cellular host factor, BST-2 (also known as CD317, HM1.24, or tetherin) and requires Vpu’s TM domain.

[11] At the cell surface, BST2 resides in lipid rafts through the GPI anchor, whereas its TM domain lies outside them, indirectly interacting with the actin cytoskeleton.

Vpu primary site of action is the plasma membrane, where this protein targets cell-surface BST-2 through their mutual TM-to-TM binding, leading to lysosomes, partially dependent on βTrCP.

The N-terminus of Vpu encoding the transmembrane (TM) anchor represents an active domain important for the regulation of virus release but not CD4 degradation.