The present invention provides chimeric protein constructs having anti-viral activity, compositions and methods of using them, and nucleic acids encoding them. The chimeric proteins include an extracellular domain of a Tetherin protein fused to the transmembrane domain, and optionally cytoplasmic tail, of a different protein. The chimeric proteins have normal anti-viral tethering activity but are resistant to inhibition by anti-Tetherins. Ex vivo methods of gene therapy are also provided.
