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 language | English (US) |
|---|---|
| Pages (from-to) | 1182-1188 |
| Number of pages | 7 |
| Journal | Molecular Therapy |
| Volume | 15 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2007 |
| Externally published | Yes |
Fingerprint
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 journal › Article
}
TY - JOUR
T1 - 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
AU - Anderson, Joseph S
AU - Li, Ming Jie
AU - Palmer, Brent
AU - Remling, Leila
AU - Li, Shirley
AU - Yam, Priscilla
AU - Yee, Jiing Kuan
AU - Rossi, John
AU - Zaia, John
AU - Akkina, Ramesh
PY - 2007/6
Y1 - 2007/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=34249336747&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34249336747&partnerID=8YFLogxK
U2 - 10.1038/sj.mt.6300157
DO - 10.1038/sj.mt.6300157
M3 - Article
C2 - 17406343
AN - SCOPUS:34249336747
VL - 15
SP - 1182
EP - 1188
JO - Molecular Therapy
JF - Molecular Therapy
SN - 1525-0016
IS - 6
ER -