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

90 Citations (Scopus)

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

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Severe Combined Immunodeficiency
Catalytic RNA
Small Interfering RNA
Transcriptional Activation
HIV
Safety
Genes
Virus Diseases
T-Lymphocytes
HIV-1
Macrophages
Clinical Trials
RNA
Transplants
Cell Line
Proteins

ASJC Scopus subject areas

  • Molecular Biology

Cite this

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

In: Molecular Therapy, Vol. 15, No. 6, 06.2007, p. 1182-1188.

Research output: Contribution to journalArticle

Anderson, Joseph S ; Li, Ming Jie ; Palmer, Brent ; Remling, Leila ; Li, Shirley ; Yam, Priscilla ; Yee, Jiing Kuan ; Rossi, John ; Zaia, John ; Akkina, Ramesh. / 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. In: Molecular Therapy. 2007 ; Vol. 15, No. 6. pp. 1182-1188.
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