Distinct genomic integration of MLV and SIV vectors in primate hematopoietic stem and progenitor cells.
Distinct genomic integration of MLV and SIV vectors in primate hematopoietic stem and progenitor cells.
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DOI：
10.1371/journal.pbio.0020423
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发表时间：
2004-12
期刊：
影响因子：
9.8
通讯作者：
Calmels B
中科院分区：
文献类型：
--
作者：
Hematti P;Hong BK;Ferguson C;Adler R;Hanawa H;Sellers S;Holt IE;Eckfeldt CE;Sharma Y;Schmidt M;von Kalle C;Persons DA;Billings EM;Verfaillie CM;Nienhuis AW;Wolfsberg TG;Dunbar CE;Calmels B
小鼠白血病病毒(MLV)衍生载体被广泛用于造血干细胞(HSC)基因转移，但慢病毒载体如猴免疫缺陷病毒(SIV)可实现更高效率的转移和更好的表达。最近对细胞系的研究挑战了逆转录病毒和逆转录病毒载体随机整合到宿主基因组中的观念。使用这些载体的医学应用是针对造血干细胞的，因此，大规模综合分析长期重新填充的造血干细胞中MLV和SIV的整合对于开发改进的整合载体至关重要。我们研究了6个月至6年前与MLV或SIV转导的CD34+细胞一起移植的恒河猴HSCs中的整合部位。将独特的MLV(491)和SIV(501)插入片段与一组电子产生的随机整合位点进行比较。虽然MLV整合子主要位于转录起始点附近，但SIV整合子强烈倾向于基因组的转录单位和基因密集区。这些整合模式建议了不同的整合机制，以及MLV与SIV载体的不同安全含义。一种灵长类的造血干细胞基因转移模型显示，MLV整合在转录起始点附近，而SIV整合到基因密集区域，这表明两种病毒都具有不同的安全性
Murine leukemia virus (MLV)-derived vectors are widely used for hematopoietic stem cell (HSC) gene transfer, but lentiviral vectors such as the simian immunodeficiency virus (SIV) may allow higher efficiency transfer and better expression. Recent studies in cell lines have challenged the notion that retroviruses and retroviral vectors integrate randomly into their host genome. Medical applications using these vectors are aimed at HSCs, and thus large-scale comprehensive analysis of MLV and SIV integration in long-term repopulating HSCs is crucial to help develop improved integrating vectors. We studied integration sites in HSCs of rhesus monkeys that had been transplanted 6 mo to 6 y prior with MLV- or SIV-transduced CD34+ cells. Unique MLV (491) and SIV (501) insertions were compared to a set of in silico-generated random integration sites. While MLV integrants were located predominantly around transcription start sites, SIV integrants strongly favored transcription units and gene-dense regions of the genome. These integration patterns suggest different mechanisms for integration as well as distinct safety implications for MLV versus SIV vectors. A primate model of gene transfer into hematopoietic stem cells demonstrated MLV integration around transcription start sites whereas SIV integrated into gene-dense regions, indicating distinct safety implications for each
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影响因子：
158.5
作者：
Hacein-Bey-Abina, S;Le Deist, F;Leiva, L
通讯作者：
Leiva, L
影响因子：
5.4
作者：
An, DS;Wersto, RP;Donahue, RE
通讯作者：
Donahue, RE
影响因子：
13.6
作者：
Dudley, JP
通讯作者：
Dudley, JP
DOI：
10.1159/000015070
发表时间：
1998-01-01
期刊：
CYTOGENETICS AND CELL GENETICS
影响因子：
--
作者：
Best, RG;Diamond, D;Moore, CM
通讯作者：
Moore, CM
影响因子：
64.5
作者：
Gilbert, N;Boyle, S;Bickmore, WA
通讯作者：
Bickmore, WA