Vpu Exploits the Cross-Talk between BST2 and the ILT7 Receptor to Suppress Anti-HIV-1 Responses by Plasmacytoid Dendritic Cells

Abstract

Plasmacytoid dendritic cells (pDCs) constitute a major source of type-I interferon (IFN-I) production during acute HIV infection. Their activation results primarily from TLR7-mediated sensing of HIV-infected cells. However, the interactions between HIV-infected T cells and pDCs that modulate this sensing process remain poorly understood. BST2/Tetherin is a restriction factor that inhibits HIV release by cross-linking virions onto infected cell surface. BST2 was also shown to engage the ILT7 pDC-specific inhibitory receptor and repress TLR7/9-mediated IFN-I production by activated pDCs. Here, we show that Vpu, the HIV-1 antagonist of BST2, suppresses TLR7-mediated IFN-I production by pDC through a mechanism that relies on the interaction of BST2 on HIV-producing cells with ILT7. Even though Vpu downregulates surface BST2 as a mean to counteract the restriction on HIV-1 release, we also find that the viral protein re-locates remaining BST2 molecules outside viral assembly sites where they are free to bind and activate ILT7 upon cell-to-cell contact. This study shows that through a targeted regulation of surface BST2, Vpu promotes HIV-1 release and limits pDC antiviral responses upon sensing of infected cells. This mechanism of innate immune evasion is likely to be important for an efficient early viral dissemination during acute infection.

Differential Control of BST2 Restriction and Plasmacytoid Dendritic Cell Antiviral Response by Antagonists Encoded by HIV-1 Group M and O Strains

“…Virion tethering by BST2 can sensitize infected cells to antibody (Ab)-dependent cell-mediated cytotoxicity (ADCC) (7)(8)(9) as well as activate proinflammatory NF-B signaling via a dual-tyrosine motif in the cytoplasmic tail of the protein (10). Moreover, the physical limitation of HIV-1 particle release by BST2 was found to stimulate IFN-I production by plasmacytoid dendritic cells (pDCs) in the context of cell contacts between HIV-1-producing cells and pDCs (11). In this regard, BST2 can act as a ligand of immunoglobulin-like transcript 7 (ILT7), a pDC-specific inhibitory receptor that downregulates Toll-like receptor 7/9 (TLR7/9)-mediated IFN-I production upon pDC activation (11,12).…”

“…Moreover, the physical limitation of HIV-1 particle release by BST2 was found to stimulate IFN-I production by plasmacytoid dendritic cells (pDCs) in the context of cell contacts between HIV-1-producing cells and pDCs (11). In this regard, BST2 can act as a ligand of immunoglobulin-like transcript 7 (ILT7), a pDC-specific inhibitory receptor that downregulates Toll-like receptor 7/9 (TLR7/9)-mediated IFN-I production upon pDC activation (11,12). Mechanistic evidence suggests that virion tethering interferes with the ability of BST2 to act in conjunction with ILT7 as a negative regulator of the IFN response by pDCs (11).…”

“…In this regard, BST2 can act as a ligand of immunoglobulin-like transcript 7 (ILT7), a pDC-specific inhibitory receptor that downregulates Toll-like receptor 7/9 (TLR7/9)-mediated IFN-I production upon pDC activation (11,12). Mechanistic evidence suggests that virion tethering interferes with the ability of BST2 to act in conjunction with ILT7 as a negative regulator of the IFN response by pDCs (11).…”

“…The short isoform lacks the first 12 N-terminal residues present in the long isoform, including conserved tyrosine and serine-threonine motifs. These isoforms have the ability to form homodimers and heterodimers, and while they display differential signaling activities (signaling is restricted to the long BST2 homodimer), they are all capable of interacting with ILT7 on pDCs (11). Primate lentivirus antagonists counteract BST2 restriction via intracellular sequestration, degradation, and/or displacement mechanisms to remove BST2 from sites of virus budding (24).…”

Assessing the Innate Sensing of HIV-1 Infected CD4⁺ T Cells by Plasmacytoid Dendritic Cells Using an <em>Ex vivo</em> Co-culture System.

“…The protocols described here measure sensing of T cells infected with GFP-tagged HIV-1 viruses that differ only in their ability to express Vpu, as described in our recent report 18 . However, these methods could easily be modified to study sensing of untagged viruses as well as viruses lacking other viral genes that could potentially modulate innate sensing.…”