UC San Diego

BST-2 (tetherin, CD317) is an interferon-inducible transmembrane protein which plays an integral role in the host cell defense against lentiviruses, including HIV-1 and HIV-2. BST-2 acts by restricting the release of budding virions at the surface of infected cells. The HIV- 1 accessory protein Vpu counteracts BST-2 activity by decreasing expression of the protein at the cell surface. HIV-2 also downregulates surface BST-2 levels, but uses instead an envelope glycoprotein. The activities of both HIV-1 Vpu and HIV-2 Env depend on clathrin-mediated endocytosis (CME): disruption of clathrin coat assembly via over-expression of the C-terminal domain of the clathrin assembly protein AP180 abrogated the downregulatory effect of Vpu and Env on BST-2. Although substantial data suggested that Vpu induces the ubiquitination of BST2 and blocks its recycling to the plasma membrane, neither knockdown of Hrs, a protein involved in the sorting of ubiquitinated surface proteins to lysosomes, nor expression of mutated versions of rab11 or rab22, regulators of endosomal recycling, blocked Vpu- activity. In addition to its role in restricting nascent virions, BST-2 also serves to stimulate NF-[kappa]B activation. This activity is also inhibited by HIV-1 Vpu or HIV-2 Env. These findings suggest that HIV-1 and HIV-2 utilize specific proteins to inhibit both the restrictive and signaling activities of BST-2