Tetherin Restricts Productive HIV-1 Cell-to-Cell Transmission

Abstract

The IFN-inducible antiviral protein tetherin (or BST-2/CD317/HM1.24) impairs release of mature HIV-1 particles from infected cells. HIV-1 Vpu antagonizes the effect of tetherin. The fate of virions trapped at the cell surface remains poorly understood. Here, we asked whether tetherin impairs HIV cell-to-cell transmission, a major means of viral spread. Tetherin-positive or -negative cells, infected with wild-type or ΔVpu HIV, were used as donor cells and cocultivated with target lymphocytes. We show that tetherin inhibits productive cell-to-cell transmission of ΔVpu to targets and impairs that of WT HIV. Tetherin accumulates with Gag at the contact zone between infected and target cells, but does not prevent the formation of virological synapses. In the presence of tetherin, viruses are then mostly transferred to targets as abnormally large patches. These viral aggregates do not efficiently promote infection after transfer, because they accumulate at the surface of target cells and are impaired in their fusion capacities. Tetherin, by imprinting virions in donor cells, is the first example of a surface restriction factor limiting viral cell-to-cell spread. Tetherin is a cell surface “restriction factor” that acts as an innate antiviral defense. Tetherin prevents newly produced particles of HIV-1 and other enveloped viruses from escaping the surface of infected cells. HIV-1 encodes the protein Vpu to counteract this host defense. We have studied here if HIV-1 particles trapped at the cell surface may be transmitted to neighboring uninfected cells. Direct transmission through cell-to-cell contacts is indeed an efficient means for viral spread. Virological synapses may be formed between infected donor cells and target cells, allowing rapid and massive transmission of viruses. We show that tetherin inhibits productive cell-to-cell transmission of Vpu-deleted HIV to target cells, and impairs that of wild-type virus. Tetherin accumulates with Gag at the contact zone between infected and target cells, but does not prevent the formation of virological synapses. With tetherin, viruses are then mostly transferred to targets as abnormally large patches that are impaired in their fusion capacities. These results represent the first example of a surface restriction factor limiting viral cell-to-cell spread, acting in donor cells, but inhibiting infection after transfer of viral material to novel recipient cells.