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Helper virus induced T cell lymphoma in nonhuman primates after retroviral mediated gene transfer
Open accessAbstract
Moloney Murine Leukemia Virus (MoMuLV) causes T cell neoplasms in rodents but is not known to be a pathogen in primates. The core protein and enzyme genes of the MoMuLV genome together with an amphotropic envelope gene are utilized to engineer the cell lines that generate retroviral vectors for use in current human gene therapy applications. We developed a producer clone that generates a very high concentration of retroviral vector particles to optimize conditions for gene insertion into pluripotent hematopoietic stem cells. This producer cell line also generates a much lower concentration of replication-competent virus that arose through recombination. Stem cells from rhesus monkeys were purified by immunoselection with an anti-CD34 antibody, incubated in vitro for 80-86 h in the presence of retroviral vector particles with accompanying replication-competent virus and used to reconstitute recipients whose bone marrow had been ablated by total body irradiation. The retroviral vector genome was detected in circulating cells of five of eight transplant recipients of CD34+ cells and in the circulating cells of two recipients of infected, unfractionated bone marrow mononuclear cells. Three recipients of CD34+ cells had a productive infection with replication-competent virus. Six or seven mo after transplantation, each of these animals developed a rapidly progressive T cell neoplasm involving the thymus, lymph nodes, liver, spleen, and bone marrow. Lymphoma cells contained 10-50 copies of the replication-competent virus, but lacked the retroviral vector genome. We conclude that replication-competent viruses arising from producer cells making retroviral vectors can be pathogenic in primates, which underscores the importance of carefully screening retroviral producer clones used in human trials to exclude contamination with replication-competent virus.
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“Although viral vectors have been widely used in the delivery of the CRISPR/Cas9 system in vitro and in vivo, their fundamental shortcomings, such as the risk of carcinogenesis, limited insertion size, immune responses and difficulty in large-scale production, severely limit their further applications.”
From Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities (2018) · cites this paper as [71]
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Metadata
- Authors
- Donahue, R. E., Kessler, S. W., Bodine, D., McDonagh, K., Dunbar, C., Goodman, S., Agricola, B., Byrne, E., Raffeld, M., & Moen, R.
- Affiliations
- National Institutes of Health (US)
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 1992-10-01
- Volume
- 176
- Issue
- 4
- Pages
- 1125-1135
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2119385
- OpenAlex
- W2132859839
- Cited by
- 532
- References
- 42
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 3 · 2022: 8 · 2021: 4 · 2020: 3 · 2019: 5 · 2018: 10 · 2017: 7 · 2015: 8 · 2014: 11 · 2013: 5 · 2012: 9
- FWCI
- 17.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and Retrovirus Studies
- Health Sciences › Medicine › Surgery › Xenotransplantation and immune response
- Keywords
- Moloney murine leukemia virus, retroviral vectors, replication-competent virus, T-cell lymphoma, helper virus, retroviral gene transfer, CD34+ hematopoietic stem cells, bone marrow transplantation, rhesus monkeys, non-human primates, gene therapy safety, thymic lymphoma
- MeSH terms
- Animals, Antibodies, Monoclonal, Antigens, Differentiation, Base Sequence, Cells, Cultured, DNA, Neoplasm, DNA, Viral, Globins, Helper Viruses, Macaca mulatta, Molecular Sequence Data, Moloney murine leukemia virus, Oligodeoxyribonucleotides, Time Factors, Transfection, Virus Replication, Antigens, CD, Bone Marrow Transplantation, Lymphoma, T-Cell, Genome, Viral, Antigens, CD34
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