Safety and efficacy of a lentiviral vector containing cthree anti-HIV genes - CCR5 ribozyme, tat-rev siRNA, and TAR decoy - In SCID-hu mouse-derived t cells

Joseph S Anderson, Ming Jie Li, Brent Palmer, Leila Remling, Shirley Li, Priscilla Yam, Jiing Kuan Yee, John Rossi, John Zaia, Ramesh Akkina

Research output: Contribution to journalArticle

91 Scopus citations

Abstract

Gene therapeutic strategies show promise in controlling human immunodeficiency virus (HIV) infection and in restoring immunological function. A number of efficacious anti-HIV gene constructs have been described so far, including small interfering RNAs (siRNAs), RNA decoys, transdominant proteins, and ribozymes, each with a different mode of action. However, as HIV is prone to generating escape mutants, the use of a single anti-HIV construct would not be adequate to afford long range-viral protection. On this basis, a combination of highly potent anti-HIV genes - namely, a short hairpin siRNA (shRNA) targeting rev and tat, a transactivation response (TAR) decoy, and a CCR5 ribozyme - have been inserted into a third-generation lentiviral vector. Our recent in vitro studies with this construct, Triple-R, established its efficacy in both T-cell lines and CD34 cell-derived macrophages. In this study, we have evaluated this combinatorial vector in vivo. Vector-transduced CD34 cells were injected into severe combined immunodeficiency (SCID)-hu mouse thy/liv grafts to determine their capacity to give rise to T cells. Our results show that phenotypically normal transgenic T cells are generated that are able to resist HIV-1 infection when challenged in vitro. These important attributes of this combinatorial vector show its promise as an excellent candidate for use in human clinical trials.

Original languageEnglish (US)
Pages (from-to)1182-1188
Number of pages7
JournalMolecular Therapy
Volume15
Issue number6
DOIs
StatePublished - Jun 2007
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology

Fingerprint Dive into the research topics of 'Safety and efficacy of a lentiviral vector containing cthree anti-HIV genes - CCR5 ribozyme, tat-rev siRNA, and TAR decoy - In SCID-hu mouse-derived t cells'. Together they form a unique fingerprint.

  • Cite this