Gene Therapy Strategies for HIV/AIDS: Preclinical Modeling in Humanized Mice
Abstract
:1. Introduction
2. An Ideal in Vivo Animal Model for HIV Gene Therapy
3. Immunodeficient Strains Used to Generate Humanized Mice
4. Currently Used Humanized Mouse Models
Model | Method (Mouse Strain) | Advantages | Disadvantages | Gene Therapy Approaches Studied |
---|---|---|---|---|
Hu-PBL | i/p injection of human PBMC. (SCID, NOD-SCID, NSG, NOG) | Easy to produce. Immediate use. Good T cell engraftment. | Lacks multilineage hematopoiesis. Lacks primary immune response. Graft versus host disease. | CCR5 shRNA [22,23] |
tat-rev shRNA [24] | ||||
vif/pol shRNA [25] | ||||
antisense env [24] | ||||
fusion inhibitor [24] | ||||
BNAb [26] | ||||
TCR [27] | ||||
TRIM5α [28] | ||||
ZFN for CCR5 [29] | ||||
ZFN for CXCR4 [30,31] | ||||
LEDGF/p75 [32] | ||||
Hu-HSC | Intrahepatic injection of CD34+ HSC into neonates. Intravenous injection of CD34+ HSC into adults. (Rag2−/− yc−/−, NSG, NOG) | Easy to produce. Multilineage hematopoiesis. Primary humoral and cellular immune responses. IgM production. Mucosal engraftment. | Weak human HLA restriction. Weak IgG production. | CCR5 shRNA [33,34] |
gag, pol shRNA [35] | ||||
tat-rev shRNA [35,36] | ||||
nef shRNA [37] | ||||
LTR shRNA [38] | ||||
antisense env [39] | ||||
TAR decoy [34] | ||||
fusion inhibitor [36] | ||||
BNAb [40] | ||||
TRIM5α [33,34] | ||||
ZFN for CCR5 [41] | ||||
SCID-Hu | Co-implantation of human fetal liver and thymic tissue under kidney capsule. (SCID or NOD-SCID) | Abundant T cell lymphopoiesis. | Surgery needed, labor intensive. Requires human fetal tissue. No multilineage hematopoiesis. No primary immune response. Poor peripheral T cell engraftment. | Integrase antibody [42] |
tat-rev shRNA [43] | ||||
rev shRNA [44] | ||||
TAR decoy [43,45] | ||||
CCR5 ribozyme [43,45,46] | ||||
tat-rev ribozyme rev aptamer [47] | ||||
CCR5 intrabody [48] | ||||
TRIM5α [28] | ||||
Transgenic TCR [49] | ||||
RevM10 [50] | ||||
BLT | Co-implantation of human fetal liver and thymic tissue under kidney capsule with additional i/v injection of autologous CD34+ HSC. (Rag2−/− yc−/−, NOD-SCID, NSG) | Multilineage hematopoiesis. Primary humoral and cellular immune responses. IgM production. Presence of human thymus. Human HLA T cell restriction. Mucosal engraftment. | Surgery needed, labor intensive. Requires human fetal tissue. Weak IgG production. | CCR5 shRNA [51,52] LTR shRNA [52] transgenic TCR [53] BNAb [54] |
5. Preclinical Gene Therapy Questions that Can be Effectively Assessed in Humanized Mice
6. Anti-HIV Gene Therapy Constructs
7. RNAi
8. Ribozymes
9. RNA Decoys and Aptamers
10. Antibodies
11. Transgenic T cell Receptors
12. Transdominant Proteins
13. Zinc finger, TALENS and CRISPR Nucleases
14. Host Restriction Factors
15. Fusion Inhibitors
16. Combinatorial Approaches
17. Clinical Studies and Future Directions
Gene therapy construct (viral or cellular target) | Proprietary name | Gene modified cells | Delivery method | Phase, status | Reference(s) |
---|---|---|---|---|---|
Antisense (env mRNA) | VRX496 | Autologous CD4+ T cells | Lentiviral vector | I-II, Ongoing | [111,112,113] |
*NCT00622232 | |||||
*NCT00295477 | |||||
*NCT00131560 | |||||
ZFN (CCR5 gene) | SB 728T | Autologous CD4+ T cells | Adenoviral vector | I-II, Ongoing | [114] |
*NCT01543152 | |||||
*NCT01252641 | |||||
*NCT01044654 | |||||
*NCT00842634 | |||||
shRNA (CCR5 mRNA) Fusion inhibitor C46 (env protein) | Cal-1 | Autologous CD34+ HSCs and CD4+ T cells | Lentiviral vector | I-II, Ongoing | [115] |
*NCT01734850 | |||||
Fusion inhibitor C46 (env protein) | M87o | Autologous of Allogeneic CD34+ HSCs | Retroviral vector | I-II, Ongoing | [116] |
*NCT00858793 | |||||
Endoribonuclease (ACA sequences) | MazF-T | Autologous CD4+ T cells | Retroviral vector | I, Ongoing | *NCT01787994 |
Transgenic TCR (gag epitope) | Autologous CD8+ T cells | Lentiviral vector | I, Ongoing | *NCT0091224 | |
Chimeric antigen receptor (gp120 protein) | Autologous CD4+ and CD8+ T cells | Retroviral vector | I-II, Completed | [117,118,119,120] | |
*NCT00001409 | |||||
*NCT01013415 | |||||
Antisense (TAR, tat/rev mRNA) | HGTV43 | Autologous CD34+ HSCs | Retroviral vector | I-II, Ongoing | [121] |
Ribozyme (tat/vpr mRNA) | OZ1 | Autologous CD34+ HSCs | Retroviral vector | II, Ongoing | [80,122] |
*NCT01177059 | |||||
*NCT00074997 | |||||
Ribozyme (tat/vpr mRNA) | Rz2 | Syngeneic CD4+ T cells | Retroviral vector | I, Completed | [108,123,124,125] |
Ribozyme (tat/rev mRNA) | Autologous CD34+ HSCs | Retroviral vector | II, Completed | *NCT00002221 | |
shRNA (tat/rev mRNA) TAR decoy (tat protein) Ribozyme (CCR5 mRNA) | Autologous CD34+ HSCs | Lentiviral vector | Pilot, Ongoing | [79] | |
*NCT01153464 | |||||
*NCT00569985 | |||||
Ribozyme (U5/pol mRNA) | MY-2 | Autologous CD4+ T cells | Retroviral vector | I, Completed | [110] |
RRE decoy (rev protein) | Autologous CD34+ HSCs | Retroviral vector | Pilot, Completed | [107] | |
Transdominant rev (rev protein) | Autologous CD34+ HSCs | Retroviral vector | I, Completed | [126,127] | |
Transdominant rev (rev protein) | Autologous CD4+ T cells | Gold particles | I, Completed | [128] | |
Transdominant rev (rev protein) | Autologous CD4+ T cells | Retroviral vector | I, Completed | [88] | |
Transdominant rev (rev protein) Antisense (pol mRNA) | Autologous CD34+ HSCs | Retroviral vector | I/II, Completed | *NCT00003942 |
Acknowledgements
Conflicts of Interest
References
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Bennett, M.S.; Akkina, R. Gene Therapy Strategies for HIV/AIDS: Preclinical Modeling in Humanized Mice. Viruses 2013, 5, 3119-3141. https://doi.org/10.3390/v5123119
Bennett MS, Akkina R. Gene Therapy Strategies for HIV/AIDS: Preclinical Modeling in Humanized Mice. Viruses. 2013; 5(12):3119-3141. https://doi.org/10.3390/v5123119
Chicago/Turabian StyleBennett, Michael S., and Ramesh Akkina. 2013. "Gene Therapy Strategies for HIV/AIDS: Preclinical Modeling in Humanized Mice" Viruses 5, no. 12: 3119-3141. https://doi.org/10.3390/v5123119
APA StyleBennett, M. S., & Akkina, R. (2013). Gene Therapy Strategies for HIV/AIDS: Preclinical Modeling in Humanized Mice. Viruses, 5(12), 3119-3141. https://doi.org/10.3390/v5123119