Targeting retroviral vector infection to cells that express heregulin receptors using a TVA-heregulin bridge protein.

Previously we have shown that it is possible to target retroviral vectors to cells using avian sarcoma and leukosis virus (ASLV) receptor-ligand and receptor-single-chain antibody bridge proteins (now designated as GATEs for guided adaptors for targeted entry). In this report we were interested in determining whether this approach can be used to deliver retroviral vectors specifically to cells that express heregulin receptors. Heregulin receptors are attractive targets for retroviral vector-based gene delivery protocols since they are often overexpressed on the surfaces of cancer cells. To explore this possibility, the TVA-herbeta1 protein was generated, consisting of the extracellular domain of the TVA receptor for ASLV-A fused to the EGF-like region of heregulin beta1. TVA-herbeta1 bound specifically to cells that express heregulin receptors, rendering them susceptible to efficient and specific infection by subgroup A ASLV vectors. In addition, these activities of TVA-herbeta1 were abrogated specifically in the presence of another bridge protein that contained the same ligand domain. These data confirm that the GATE protein TVA-herbeta1 mediates targeted retroviral infection via cell surface heregulin receptors.