Overexpression of inactive tetherin delGPI mutant inhibits HIV-1 Vpu-mediated antagonism of endogenous tetherin

Tetherin/BST-2/CD317 inhibits HIV-1 release from infected cells, but the viral Vpu protein efficiently antagonizes this antiviral activity through direct interaction between the transmembrane (TM) domains of each protein. Here, we demonstrated that overexpression of an inactive tetherin delGPI mutant, the TM domain of which could competitively block Vpu targeting of endogenous tetherin, potently inhibited HIV-1 release from human tetherin-positive cells in both transient and stable expression conditions. These results also suggest that heterologous dimerization occurred between the delGPI mutant and endogenous tetherin. These findings suggest that blocking the Vpu/tetherin interface may be a novel therapeutic approach against HIV-1 release.Structured summary of protein interactionsVpu and Tetherin colocalize by fluorescence microscopy (View interaction) Tetherin physically interacts with Vpu by anti tag coimmunoprecipitation (View interaction)

► Tetherin delGPI mutant potently inhibits HIV-1 release in tetherin-positive cells.
► Transmembrane domain of tetherin delGPI blocks Vpu/endogenous tetherin interaction.
► The tetherin delGPI mutant may heterodimerize with endogenous tetherin.
► Blocking the Vpu/tetherin interface would be a feasible HIV-1 therapeutic target.