Zinc-finger nuclease editing of human cxcr4 promotes HIV-1 CD4(+) T cell resistance and enrichment
Open accessAbstract
HIV-1-infected individuals can harbor viral isolates that can use CCR5, as well as CXCR4, for viral entry. To genetically engineer HIV-1 resistance in CD4(+) T cells, we assessed whether transient, adenovirus delivered zinc-finger nuclease (ZFN) disruption of genomic cxcr4 or stable lentiviral expression of short hairpin RNAs (shRNAs) targeting CXCR4 mRNAs provides durable resistance to HIV-1 challenge. ZFN-modification of cxcr4 in CD4(+) T cells was found to be superior to cell integrated lentivirus-expressing CXCR4 targeting shRNAs when CD4(+) T cells were challenged with HIV-1s that utilizes CXCR4 for entry. Cxcr4 disruption in CD4(+) T cells was found to be stable, conferred resistance, and provided for continued cell enrichment during HIV-1 infection in tissue culture and, in vivo, in peripheral blood mononuclear cell transplanted NSG mice. Moreover, HIV-1-infected mice with engrafted cxcr4 ZFN-modified CD4(+) T cells demonstrated lower viral levels in contrast to mice engrafted with unmodified CD4(+) T cells. These findings provide evidence that ZFN-mediated disruption of cxcr4 provides a selective advantage to CD4(+) T cells during HIV-1 infection.
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Many studies have successfully disrupted CCR5 in various cell lines, primary T cells and hematopoietic stem cells, as well as in humanized mice.
“Since then, many studies have successfully disrupted CCR5 in various cell lines, primary T cells and hematopoietic stem cells (HSCs), as well as in humanized mice [30,31,32,38,39,40].”
From Newer Gene Editing Technologies toward HIV Gene Therapy (2013) · cites this paper as [32]
Three studies have demonstrated that targeting CXCR4 can promote HIV-1 resistance.
“To date, three studies have demonstrated that targeting CXCR4 can promote HIV-1 resistance.”
From Newer Gene Editing Technologies toward HIV Gene Therapy (2013) · cites this paper as [32]
An adenoviral vector delivered ZFNs to activated CD4+ T cells in vitro, reaching a gene-disruption efficiency as high as 54% for CCR5 and 30%-34% for CXCR4.
“As a proof-of-concept delivery method, an adenoviral vector was used to deliver ZFNs to activated CD4+T cells in vitro, reaching a gene-disruption efficiency as high as 54% for CCR5 [30] and 30%–34% for CXCR4 [31,32].”
From Newer Gene Editing Technologies toward HIV Gene Therapy (2013) · cites this paper as [32]
After expansion in vitro, adenovirus-ZFN transduced CD4+ T cells infused into humanized mice were able to establish resistance to HIV-1 infection.
“After expansion in vitro, the adenovirus-ZFN transduced CD4+ T cells were infused into humanized mice where they were able to establish resistance to HIV-1 infection.”
From Newer Gene Editing Technologies toward HIV Gene Therapy (2013) · cites this paper as [32]
Cites
HIV-1 Entry Cofactor: Functional cDNA Cloning of a Seven-Transmembrane, G Protein-Coupled Receptor
Feng, Y. Y., Broder, C. C., Kennedy, P. E., & Berger, E. A. (1996) · Science · doi:10.1126/science.272.5263.872 · Cited by 4,169 · see citing works
Orimo, A., Gupta, P. B., Sgroi, D. C., Arenzana-Seisdedos, F., Delaunay, T., Naeem, R., Carey, V. J., Richardson, A. L., & Weinberg, R. A. (2005) · Cell · doi:10.1016/j.cell.2005.02.034 · Cited by 3,759 · see citing works
Identification of a major co-receptor for primary isolates of HIV-1
Deng, H., Liu, R., Ellmeier, W., Choe, S. S., Unutmaz, D., Burkhart, M. D., Marzio, P. D., Marmon, S., Sutton, R. E., Hill, C. M., et al. (1996) · Nature · doi:10.1038/381661a0 · Cited by 3,640 · see citing works
Nagasawa, T., Hirota, S., Tachibana, K., Takakura, N., Nishikawa, S.-I., Kitamura, Y., Yoshida, N., Kikutani, H., & Kishimoto, T. (1996) · Nature · doi:10.1038/382635a0 · Cited by 2,338 · see citing works
Genome editing with engineered zinc finger nucleases
Urnov, F. D., Rebar, E. J., Holmes, M. C., Zhang, H. S., & Gregory, P. D. (2010) · Nature Reviews Genetics · doi:10.1038/nrg2842 · Cited by 2,285 · see citing works
Self-citationLong-Term Control of HIV by CCR5 Delta32/Delta32 Stem-Cell Transplantation
Hütter, G., Nowak, D., Mossner, M., Ganepola, S., Muessig, A., Allers, K., Schneider, T., Hofmann, J., Kücherer, C., Blau, O., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0802905 · Cited by 1,837 · see citing works
Highly efficient endogenous human gene correction using designed zinc-finger nucleases
Urnov, F. D., Miller, J. C., Lee, Y.-L., Beausejour, C. M., Rock, J. M., Augustus, S., Jamieson, A. C., Porteus, M. H., Gregory, P. D., & Holmes, M. C. (2005) · Nature · doi:10.1038/nature03556 · Cited by 1,642 · see citing works
Self-citationThe role of a mutant CCR5 allele in HIV–1 transmission and disease progression
Huang, Y., Paxton, W. A., Wolinsky, S. M., Neumann, A. U., Zhang, L., Tian, H., Kang, S., Ceradini, D. J., Jin, Z., Yazdanbakhsh, K., et al. (1996) · Nature Medicine · doi:10.1038/nm1196-1240 · Cited by 1,359 · see citing works
HIV Infection, Inflammation, Immunosenescence, and Aging
Deeks, S. G. (2011) · Annual Review of Medicine · doi:10.1146/annurev-med-042909-093756 · Cited by 1,349 · see citing works
CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5
Wu, L., Gerard, N. P., Wyatt, R. T., Choe, H., Parolin, C., Ruffing, N., Borsetti, A., Cardoso, A. A., Desjardin, E., Newman, W., et al. (1996) · Nature · doi:10.1038/384179a0 · Cited by 1,168 · see citing works
An improved zinc-finger nuclease architecture for highly specific genome editing
Miller, J. C., Holmes, M. C., Wang, J., Guschin, D. Y., Lee, Y.-L., Rupniewski, I., Beausejour, C. M., Waite, A. J., Wang, N. S., Kim, K. A., et al. (2007) · Nature Biotechnology · doi:10.1038/nbt1319 · Cited by 1,051 · see citing works
Self-citationEstablishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases
Perez, E. E., Wang, J., Miller, J. C., Jouvenot, Y., Kim, K. A., Liu, O., Wang, N., Lee, G., Bartsevich, V. V., Lee, Y.-L., et al. (2008) · Nature Biotechnology · doi:10.1038/nbt1410 · Cited by 999 · see citing works
Self-citationEnhancing Gene Targeting with Designed Zinc Finger Nucleases
Bibikova, M. V., Beumer, K. J., Trautman, J. K., & Carroll, D. (2003) · Science · doi:10.1126/science.1079512 · Cited by 824 · see citing works
Qin, F. X.-F., An, D. S., Chen, I. S. Y., & Baltimore, D. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.232688199 · Cited by 701 · see citing works
Holt, N., Wang, J., Kim, K., Friedman, G., Wang, X., Taupin, V., Crooks, G. M., Kohn, D. B., Gregory, P. D., Holmes, M. C., et al. (2010) · Nature Biotechnology · doi:10.1038/nbt.1663 · Cited by 677 · see citing works
Self-citationMiyoshi, H., Smith, K. A., Mosier, D., Verma, I., & Torbett, B. (1999) · Science · doi:10.1126/science.283.5402.682 · Cited by 668 · see citing works
Self-citationT Cell-Specific siRNA Delivery Suppresses HIV-1 Infection in Humanized Mice
Kumar, P., Ban, H., Kim, S. S., Wu, H., Pearson, T., Greiner, D. L., Laouar, A., Yao, J., Haridas, V., Habiro, K., et al. (2008) · Cell · doi:10.1016/j.cell.2008.06.034 · Cited by 573 · see citing works
A Rapid and General Assay for Monitoring Endogenous Gene Modification
Guschin, D. Y., Waite, A. J., Katibah, G. E., Miller, J. C., Holmes, M. C., & Rebar, E. J. (2010) · Methods in molecular biology · doi:10.1007/978-1-60761-753-2_15 · Cited by 500 · see citing works
Self-citationSmith, J. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.17.3361 · Cited by 425 · see citing works
Subgroup Analyses of Maraviroc in Previously Treated R5 HIV-1 Infection
Fätkenheuer, G., Nelson, M. R., Lazzarin, A., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0803154 · Cited by 365 · see citing works
Dar, A., Kollet, Ó., & Lapidot, T. (2006) · Experimental Hematology · doi:10.1016/j.exphem.2006.04.002 · Cited by 356 · see citing works
RNAi-mediated CCR5 Silencing by LFA-1-targeted Nanoparticles Prevents HIV Infection in BLT Mice
Kim, S. S., Peer, D., Kumar, P., Subramanya, S., Wu, H., Asthana, D., Habiro, K., Yang, Y., Manjunath, N., Shimaoka, M., et al. (2009) · Molecular Therapy · doi:10.1038/mt.2009.271 · Cited by 207 · see citing works
Shimizu, S., Hong, P. W.-P., Balamurugan, A., et al. (2009) · Blood · doi:10.1182/blood-2009-04-215855 · Cited by 150 · see citing works
Engineering HIV-resistant human CD4+ T cells with CXCR4-specific zinc-finger nucleases
Wilen, C. B., Wang, J., Tilton, J. C., Miller, J. C., Kim, K. A., Rebar, E. J., Sherrill-Mix, S. A., Patro, S. C., Secreto, A. J., Jordan, A. P. O., et al. (2011) · PLoS Pathogens · doi:10.1371/journal.ppat.1002020 · Cited by 142 · see citing works
SDF-1/CXCR4 and VLA-4 interaction regulates homing in Waldenstrom macroglobulinemia
Ngo, H. T., Leleu, X. P., Lee, J. Y., Jia, X., Melhem, M. R., Runnels, J. M., Moreau, A., Burwick, N. R., Azab, A. K., Roccaro, A. M., et al. (2008) · Blood · doi:10.1182/blood-2007-12-129395 · Cited by 130 · see citing works
Nilsson, M., Ljungberg, J., Richter, J., Kiefer, T., Magnusson, M., Lieber, A., Widegren, B., Karlsson, S., & Fan, X. (2004) · The Journal of Gene Medicine · doi:10.1002/jgm.543 · Cited by 129 · see citing works
Adenoviral-mediated gene transfer in lymphocytes
Leon, R. P., Hedlund, T. E., Meech, S. J., Li, S., Schaack, J. B., Hunger, S. P., Duke, R. C., & DeGregori, J. V. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.22.13159 · Cited by 127 · see citing works
hu‐PBL‐SCID Mice: A Model for Human Immune Function, AIDS, and Lymphomagenesis
Torbett, B. E., Picchio, G., & Mosier, D. E. (1991) · Immunological Reviews · doi:10.1111/j.1600-065x.1991.tb00620.x · Cited by 116 · see citing works
Self-citationSteinberger, P., Andris‐Widhopf, J., Bühler, B., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.2.805 · Cited by 113 · see citing works
Melby, T., DeSpirito, M., DeMasi, R., Heilek‐Snyder, G., Greenberg, M. L., & Graham, N. (2006) · The Journal of Infectious Diseases · doi:10.1086/504693 · Cited by 112 · see citing works
Tilton, J. C., Wilen, C. B., Didigu, C. A., Sinha, R., Harrison, J. E., Agrawal-Gamse, C., Henning, E. A., Bushman, F. D., Martin, J. N., Deeks, S. G., et al. (2010) · Journal of Virology · doi:10.1128/jvi.01109-10 · Cited by 110 · see citing works
Current status of gene therapy strategies to treat HIV/AIDS
Strayer, D. S., Akkina, R., Bunnell, B. A., Dropulić, B., Planelles, V., Pomerantz, R. J., Rossi, J. J., & Zaia, J. A. (2005) · Molecular Therapy · doi:10.1016/j.ymthe.2005.01.020 · Cited by 106 · see citing works
Bai, J., Gorantla, S., Banda, N. K., Cagnon, L., Rossi, J. J., & Akkina, R. (2000) · Molecular Therapy · doi:10.1006/mthe.2000.0038 · Cited by 99 · see citing works
Anderson, J. S., & Akkina, R. (2005) · AIDS Research and Therapy · doi:10.1186/1742-6405-2-1 · Cited by 95 · see citing works
Hütter, G., & Thiel, E. (2011) · AIDS · doi:10.1097/qad.0b013e328340fe28 · Cited by 91 · see citing works
Potent Suppression of HIV Type 1 Infection By a Short Hairpin Anti-CXCR4 siRNA
Anderson, J. S., Banerjea, A. C., Planelles, V., & Akkina, R. (2003) · AIDS Research and Human Retroviruses · doi:10.1089/088922203322280928 · Cited by 85 · see citing works
T-cell protection and enrichment through lentiviral CCR5 intrabody gene delivery
Swan, C. H., Bühler, B., Tschan, M. P., Barbas, C. F., & Torbett, B. E. (2006) · Gene Therapy · doi:10.1038/sj.gt.3302801 · Cited by 83 · see citing works
Self-citationvan Lunzen, J., Glaunsinger, T., Stahmer, I., von Baehr, V., Baum, C., Schilz, A., Kuehlcke, K., Naundorf, S., Martinius, H., Hermann, F., et al. (2007) · Molecular Therapy · doi:10.1038/mt.sj.6300124 · Cited by 81 · see citing works
Anderson, J. S., & Akkina, R. (2005) · Retrovirology · doi:10.1186/1742-4690-2-53 · Cited by 74 · see citing works
Chung, S.-H., Seki, K., Choi, B.-I., et al. (2010) · Arthritis Research & Therapy · doi:10.1186/ar3158 · Cited by 66 · see citing works
HIV-1 infection and antiretroviral therapies: risk factors for osteoporosis and bone fracture
Ofotokun, I., & Weitzmann, M. N. (2010) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0b013e32833f48d6 · Cited by 65 · see citing works
Anderson, J. S., & Akkina, R. (2007) · Gene Therapy · doi:10.1038/sj.gt.3302958 · Cited by 62 · see citing works
Gene therapy for HIV infection: what does it need to make it work?
von Laer, D., Hasselmann, S., & Hasselmann, K. (2006) · The Journal of Gene Medicine · doi:10.1002/jgm.908 · Cited by 52 · see citing works
Pino, S. C., Brehm, M. A., Covassin-Barberis, L., et al. (2006) · Methods in molecular biology · doi:10.1007/978-1-60761-058-8_7 · Cited by 50 · see citing works
Characterization of a potent non-cytotoxic shRNA directed to the HIV-1 co-receptor CCR5
Shimizu, S., Kamata, M., Kittipongdaja, P., et al. (2009) · Genetic Vaccines and Therapy · doi:10.1186/1479-0556-7-8 · Cited by 44 · see citing works
Huang, W., Toma, J., Stawiski, E. W., et al. (2009) · AIDS Research and Human Retroviruses · doi:10.1089/aid.2008.0252 · Cited by 40 · see citing works
Multivalent Anti-CCR5 Ribozymes for Stem Cell-Based HIV Type 1 Gene Therapy
Bai, J., Rossi, J. J., & Akkina, R. (2001) · AIDS Research and Human Retroviruses · doi:10.1089/088922201750102427 · Cited by 40 · see citing works
Fransen, S., Bridger, G. J., Whitcomb, J. M., et al. (2008) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01226-07 · Cited by 30 · see citing works
Tamhane, M. C., & Akkina, R. (2008) · AIDS Research and Therapy · doi:10.1186/1742-6405-5-16 · Cited by 25 · see citing works
Can gene delivery close the door to HIV‐1 entry after escape?
Swan, C. H., & Torbett, B. E. (2006) · Journal of Medical Primatology · doi:10.1111/j.1600-0684.2006.00172.x · Cited by 11 · see citing works
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Voit, R. A., McMahon, M. A., Sawyer, S. L., & Porteus, M. H. (2013) · Molecular Therapy · doi:10.1038/mt.2012.284 · Cited by 74 · see citing works
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- Authors
- Yuan, J., Wang, J., Crain, K., Fearns, C., Kim, K. A., Hua, K. L., Gregory, P. D., Holmes, M. C., & Torbett, B. E.
- Affiliations
- Scripps Research Institute (US)
- Sangamo BioSciences (United States) (US)
- Corresponding author
- Torbett, Bruce E
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2012-04
- Volume
- 20
- Issue
- 4
- Pages
- 849-859
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC3321595
- OpenAlex
- W2086233199
- Cited by
- 105
- References
- 50
- Citations by year
- 2024: 1 · 2023: 5 · 2022: 9 · 2021: 5 · 2020: 4 · 2019: 3 · 2018: 7 · 2017: 14 · 2016: 12 · 2015: 20 · 2014: 9 · 2013: 11 · 2012: 5
- FWCI
- 6.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5t32ai007354-30)
- National Heart, Lung, and Blood Institute (HL091219, R01HL091219)
- National Institute of Allergy and Infectious Diseases (T32-AI007354., 5T32A1007354T32AI007354, P30AI036214)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- zinc finger nucleases, CXCR4, HIV-1 resistance, CD4+ T cells, genome editing, shRNA, CCR5, viral entry, HIV-1 infection, NSG mice, hematopoietic stem cell transplantation, viral load, HIV-1 tropism
- MeSH terms
- Adenoviridae, Animals, Cells, Cultured, Endonucleases, Humans, CD4-Positive T-Lymphocytes, HIV-1, Zinc Fingers, Receptors, CXCR4, RNA, Small Interfering, Mice
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