Redirecting retroviral tropism by insertion of short, nondisruptive peptide ligands into envelope
Biochemistry & Molecular Pharmacology
Graduate School of Biomedical Sciences; Programs in Gene Function and Expression and in Molecular Medicine
Medical Subject Headings
3T3 Cells; Amino Acid Sequence; Animals; Genetic Vectors; Humans; Integrins; Ligands; Mice; Molecular Sequence Data; Moloney murine leukemia virus; Oligopeptides; Recombinant Fusion Proteins; Recombination, Genetic; Retroviridae; Transduction, Genetic; Tumor Cells, Cultured; Viral Envelope Proteins
Life Sciences | Medicine and Health Sciences
A potentially powerful approach for in vivo gene delivery is to target retrovirus to specific cells through interactions between cell surface receptors and appropriately modified viral envelope proteins. Previously, relatively large (>100 residues) protein ligands to cell surface receptors have been inserted at or near the N terminus of retroviral envelope proteins. Although viral tropism could be altered, the chimeric envelope proteins lacked full activity, and coexpression of wild-type envelope was required for production of transducing virus. Here we analyze more than 40 derivatives of ecotropic Moloney murine leukemia virus (MLV) envelope, containing insertions of short RGD-containing peptides, which are ligands for integrin receptors. In many cases pseudotyped viruses containing only the chimeric envelope protein could transduce human cells. The precise location, size, and flanking sequences of the ligand affected transduction specificity and efficiency. We conclude that retroviral tropism can be rationally reengineered by insertion of short peptide ligands and without the need to coexpress wild-type envelope.
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Citation: J Virol. 2002 Apr;76(7):3558-63.