Preclinical safety and efficacy of an anti-HIV-1 lentiviral vector containing a short hairpin RNA to CCR5 and the C46 fusion inhibitor

Orit Wolstein, Maureen Boyd, Michelle Millington, Helen Impey, Joshua Boyer, Annett Howe, Frederic Delebecque, Kenneth Cornetta, Michael Rothe, Christopher Baum, Tamara Nicolson, Rachel Koldej, Jane Zhang, Naomi Keech, Joanna Camba Colón, Louis Breton, Jeffrey Bartlett, Dong Sung An, Irvin Sy Chen, Bryan BurkeGeoff P. Symonds

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Gene transfer has therapeutic potential for treating HIV-1 infection by generating cells that are resistant to the virus. We have engineered a novel self-inactivating lentiviral vector, LVsh5/C46, using two viral-entry inhibitors to block early steps of HIV-1 cycle. The LVsh5/C46 vector encodes a short hairpin RNA (shRNA) for downregulation of CCR5, in combination with the HIV-1 fusion inhibitor, C46. We demonstrate here the effective delivery of LVsh5/C46 to human T cell lines, peripheral blood mononuclear cells, primary CD4 + T lymphocytes, and CD34 + hematopoietic stem/progenitor cells (HSPC). CCR5-targeted shRNA (sh5) and C46 peptide were stably expressed in the target cells and were able to effectively protect gene-modified cells against infection with CCR5-and CXCR4-tropic strains of HIV-1. LVsh5/C46 treatment was nontoxic as assessed by cell growth and viability, was noninflammatory, and had no adverse effect on HSPC differentiation. LVsh5/C46 could be produced at a scale sufficient for clinical development and resulted in active viral particles with very low mutagenic potential and the absence of replication-competent lentivirus. Based on these in vitro results, plus additional in vivo safety and efficacy data, LVsh5/C46 is now being tested in a phase 1/2 clinical trial for the treatment of HIV-1 disease.

Original languageEnglish (US)
Article number11
Pages (from-to)11
Number of pages1
JournalMolecular Therapy - Methods and Clinical Development
Volume1
DOIs
StatePublished - Jan 8 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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    Wolstein, O., Boyd, M., Millington, M., Impey, H., Boyer, J., Howe, A., Delebecque, F., Cornetta, K., Rothe, M., Baum, C., Nicolson, T., Koldej, R., Zhang, J., Keech, N., Camba Colón, J., Breton, L., Bartlett, J., An, D. S., Chen, I. S., ... Symonds, G. P. (2014). Preclinical safety and efficacy of an anti-HIV-1 lentiviral vector containing a short hairpin RNA to CCR5 and the C46 fusion inhibitor. Molecular Therapy - Methods and Clinical Development, 1, 11. [11]. https://doi.org/10.1038/mtm.2013.11