title: The HIV-1 Vpu viroporin inhibitor BIT225 does not affect Vpu-mediated tetherin antagonism.
abstract: Among its many roles, the HIV-1 accessory protein Vpu performs a viroporin function and also antagonizes the host cell restriction factor tetherin through its transmembrane domain. BIT225 is a small molecule inhibitor that specifically targets the Vpu viroporin function, which, in macrophages, resulted in late stage inhibition of virus release and decreased infectivity of released virus, a phenotype similar to tetherin-mediated restriction. Here, we investigated whether BIT225 might mediate its antiviral function, at least in part, via inhibition of Vpu-mediated tetherin antagonism. Using T-cell lines inducible for tetherin expression, we found that BIT225 does not exert its antiviral function by inhibiting Vpu-mediated tetherin downmodulation from the cell surface, the main site of action of tetherin activity. In addition, results from a bioluminescence resonance energy transfer (BRET) assay showed that the Vpu-tetherin interaction was not affected by BIT225. Our data provide support for the concept that tetherin antagonism and viroporin function are separable on the Vpu transmembrane and that viroporin function might be cell-type dependent. Further, this work contributes to the characterization of BIT225 as an inhibitor that specifically targets the viroporin function of Vpu.
authors: McGill University AIDS Center, Lady Davis Institute, Jewish General Hospital, Montréal, Quebec, Canada.
authors: Björn D
authors: BD
authors: Kuhl
authors: Vicky
authors: V
authors: Cheng
authors: Daniel A
authors: DA
authors: Donahue
authors: Richard D
authors: RD
authors: Sloan
authors: Chen
authors: C
authors: Liang
authors: John
authors: J
authors: Wilkinson
authors: Mark A
authors: MA
authors: Wainberg
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D019791:Guanidine / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D054298:Human Immunodeficiency Virus Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000494:pharmacology*; D054334:Viral Regulatory and Accessory Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology*; D057074:Virus Release / Q000187:drug effects; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
chemical_list: D019380:Anti-HIV Agents; D015703:Antigens, CD; D058851:GPI-Linked Proteins; D019791:Guanidine; D006146:Guanidines; D054298:Human Immunodeficiency Virus Proteins; D011720:Pyrazoles; D054334:Viral Regulatory and Accessory Proteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C570889:N-(5-(1-methyl-1H-pyrazol-4-yl)-napthalene-2-carbonyl)guanidine; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins