The Interferon-Induced Protein BST-2 Restricts HIV-1 Release and Is Downregulated from the Cell Surface by the Viral Vpu Protein

Abstract

The HIV-1 accessory protein Vpu counteracts a host factor that restricts virion release from infected cells. Here we show that the interferon-induced cellular protein BST-2/HM1.24/CD317 is such a factor. BST-2 is downregulated from the cell surface by Vpu, and BST-2 is specifically expressed in cells that support the vpu phenotype. Exogenous expression of BST-2 inhibits HIV-1 virion release, while suppression of BST-2 relieves the requirement for Vpu. Downregulation of BST-2 requires both the transmembrane/ion channel domain and conserved serines in the cytoplasmic domain of Vpu. Endogenous BST-2 colocalizes with the HIV-1 structural protein Gag in endosomes and at the plasma membrane, suggesting that BST-2 traps virions within and on infected cells. The unusual structure of BST-2, which includes a transmembrane domain and a lumenal GPI anchor, may allow it to retain nascent enveloped virions on cellular membranes, providing a mechanism of viral restriction counteracted by a specific viral accessory protein.

The role of BST‐2/Tetherin in host protection and disease manifestation

“…In 2008, two independent laboratories showed that cell type‐specific expression of BST‐2 correlates with Vpu‐dependent release of HIV‐1. Suppression of endogenous BST‐2 expression resulted in Vpu‐independent virus release whereas rescue of expression with exogenous BST‐2 in cells that otherwise do not have high BST‐2 renders these cells Vpu‐dependent for virus release 6, 7. These findings revealed that BST‐2 is an inhibitor of virus release and a target of Vpu 6, 7.…”

“…In 2008, BST‐2 was rediscovered as the host factor responsible for preventing the release of HIV‐1 with mutated Vpu (HIV‐1 ΔVpu) from host cells 6, 7. Following these discoveries, BST‐2 was renamed tetherin 7.…”

“…Following virus tethering, BST‐2 facilitates virus internalization to early endosomes and subsequent lysosomal degradation. The resulting viral products serve as PAMPs that activate TLRs 6, 48, 49 (Fig. 2 #3).…”

Oligomerization state and supramolecular structure of the HIV‐1 Vpu protein transmembrane segment in phospholipid bilayers

“…Recent experiments indicate that Vpu facilitates viral budding through interactions with host cell proteins that otherwise inhibit viral budding, 35 in particular an integral membrane protein dubbed tetherin, CD317, or BST-2. 36,37 Tetherin tethers budding virions to host cells by linking the viral and host cell membranes. 38 Vpu interferes with tetherin by targeting tetherin for degradation, in a manner similar to that by which Vpu downregulates CD4.…”

Full-length Vpu and human CD4(372–433) in phospholipid bilayers as seen by magic angle spinning NMR

“…Vpu was classified as a class IA viroporin (Fischer et al, 2012;Luis Nieva et al, 2012). Recently it was found that Vpu antagonizes tetherin, a cellular antiviral defense factor that cross-links budding virions to the host cell membrane and thus inhibits virus release (Neil et al, 2008;Van Damme et al, 2008).…”