The Nef Protein of the Macrophage Tropic HIV-1 Strain AD8 Counteracts Human BST-2/Tetherin

Abstract

Bone Marrow Stromal Cell Antigen 2 (BST-2)/tetherin inhibits the release of numerous enveloped viruses by physically tethering nascent particles to infected cells during the process of viral budding from the cell surface. Tetherin also restricts human immunodeficiency virus (HIV), and pandemic main (M) group HIV type 1s (HIV-1s) are thought to rely exclusively on their Vpu proteins to overcome tetherin-mediated restriction of virus release. However, at least one M group HIV-1 strain, the macrophage-tropic primary AD8 isolate, is unable to express Vpu due to a mutation in its translation initiation codon. Here, using primary monocyte-derived macrophages (MDMs), we show that AD8 Nef protein can compensate for the absence of Vpu and restore virus release to wild type levels. We demonstrate that HIV-1 AD8 Nef reduces endogenous cell surface tetherin levels, physically separating it from the site of viral budding, thus preventing HIV retention. Mechanistically, AD8 Nef enhances internalisation of the long isoform of human tetherin, leading to perinuclear accumulation of the restriction factor. Finally, we show that Nef proteins from other HIV strains also display varying degrees of tetherin antagonism. Overall, we show that M group HIV-1s can use an accessory protein other than Vpu to antagonise human tetherin.

Small CD4 mimetics sensitize HIV-1-infected macrophages to antibody-dependent cellular cytotoxicity

“…Thus, with respect to BST-2 modulation, Vpu performs parallel roles on CD4 + T cells and macrophages. Of note, we observed that for HIV-1 AD8 and YU2, full recovery of BST-2 levels at the cell surface required Nef deletion (N-U-), in agreement with a recent report suggesting that Nef from some HIV-1 strains, including AD8 can downregulate BST-2 (Giese et al, 2020).…”

Small CD4 mimetics sensitize HIV-1-infected macrophages to antibody-dependent cellular cytotoxicity

“…Of note, we observed that for HIV-1 AD8 and YU2, full recovery of BST-2 levels at the cell surface required Nef deletion (N–U–), in agreement with a recent report suggesting that Nef from some HIV-1 strains, including AD8, can downregulate BST-2. 38 …”

Multi-functional BST2/tetherin against HIV-1, other viruses and LINE-1

“…A direct BST2-Nef interaction separates BST2 from virus-release sites at the plasma membrane through endocytosis and promotes BST2 lysosomal degradation ( Serra-Moreno et al., 2013 ). The M group HIV-1 strain AD8, unable to express Vpu owing to a mutation, utilizes Nef to enhance BST2 internalization and perinuclear accumulation without BST2 degradation ( Giese et al., 2020 ). Although the specific mechanism is not fully known, the available results show that neither Env nor Nef can decrease BST2 through the ubiquitin-proteasome system, suggesting that BST2 presents a barrier to initial HIV transmission to humans.…”