Lentivirus-mediated Gene Transfer in Hematopoietic Stem Cells Is Impaired in SHIV-infected, ART-treated Nonhuman Primates.
Lentivirus-mediated Gene Transfer in Hematopoietic Stem Cells Is Impaired in SHIV-infected, ART-treated Nonhuman Primates.
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在感染 SHIV、接受 ART 治疗的非人类灵长类动物中，慢病毒介导的造血干细胞基因转移受到损害。
DOI：
10.1038/mt.2015.19
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Kiem,Hans-Peter
中科院分区：
文献类型：
--
作者：
Younan,PatrickM;Peterson,ChristopherW;Polacino,Patricia;Kowalski,JohnP;Obenza,Willimark;Miller,HannahW;Milless,BrianP;Gafken,Phil;DeRosa,StephenC;Hu,Shiu-Lok;Kiem,Hans-Peter
最近的研究表明，基因修饰的造血干细胞（HSCs）可以减少HIV病毒血症。我们已经开发了一个HIV/AIDS患者模型，在猿猴/人类免疫缺陷病毒（SHIV）感染的猪尾猕猴，稳定抑制抗逆转录病毒治疗（ART：雷特格韦，恩曲他滨和替诺福韦）。在SHIV感染和ART之后，动物经历用表达mC 46抗HIV融合蛋白的慢病毒转导的分化簇（CD）34+细胞的自体HSC移植（HSCT）。我们表明，SHIV+，ART治疗的动物HSCT后的基因标记水平非常低。转导前CD 34+细胞含有可检测水平的所有三种ART药物，可能导致基因转移效率低。HSCT恢复和ART停止后，血浆病毒血症反弹，表明清髓性全身照射不能完全消除自体HSCT后的病毒库。在SHIV+ ART处理的猕猴中，自体HSCT后的恢复动力学与对照动物移植后观察到的恢复动力学相同。然而，T细胞亚群分析表明HSCT后表达C-C趋化因子受体5（CCR 5）的CD 4 + T细胞百分比较高。这些数据表明，延长ART中断时间可能是更有效的慢病毒转导所必需的。为了避免在HSCT后高百分比的CD 4 + CCR 5 + T细胞的情况下与ART中断相关的并发症，使用不受残余ART存在损害的载体系统也可能是有益的。
Recent studies have demonstrated that genetically modified hematopoietic stem cells (HSCs) can reduce HIV viremia. We have developed an HIV/AIDS-patient model in Simian/human immunodeficiency virus (SHIV)-infected pigtailed macaques that are stably suppressed on antiretroviral therapy (ART: raltegravir, emtricitabine and tenofovir). Following SHIV infection and ART, animals undergo autologous HSC transplantation (HSCT) with lentivirally transduced cluster of differentiation (CD)34+cells expressing the mC46 anti-HIV fusion protein. We show that SHIV+, ART-treated animals had very low gene marking levels after HSCT. Pretransduction CD34+cells contained detectable levels of all three ART drugs, likely contributing to the low gene transfer efficiency. Following HSCT recovery and the cessation of ART, plasma viremia rebounded, indicating that myeloablative total body irradiation cannot completely eliminate viral reservoirs after autologous HSCT. The kinetics of recovery following autologous HSCT in SHIV+, ART-treated macaques paralleled those observed following transplantation of control animals. However, T-cell subset analyses demonstrated a high percentage of C-C chemokine receptor 5 (CCR5)-expressing CD4+T-cells after HSCT. These data suggest that an extended ART interruption time may be required for more efficient lentiviral transduction. To avoid complications associated with ART interruption in the context of high percentages of CD4+CCR5+T-cells after HSCT, the use of vector systems not impaired by the presence of residual ART may also be beneficial.
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影响因子：
6.7
作者：
Mavigner M;Watkins B;Lawson B;Lee ST;Chahroudi A;Kean L;Silvestri G
通讯作者：
Silvestri G
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影响因子：
2.8
作者：
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DOI：
10.1182/asheducation-2013.1.389
发表时间：
2013
期刊：
Hematology. American Society of Hematology. Education Program
影响因子：
--
作者：
J. Zaia;S. Forman
通讯作者：
S. Forman
影响因子：
23.9
作者：
Kiem, Hans-Peter;Jerome, Keith R.;Deeks, Steven G.;McCune, Joseph M.
通讯作者：
McCune, Joseph M.
DOI：
10.1056/nejmoa1300662
发表时间：
2014-03-06
期刊：
The New England journal of medicine
影响因子：
--
作者：
Tebas P;Stein D;Tang WW;Frank I;Wang SQ;Lee G;Spratt SK;Surosky RT;Giedlin MA;Nichol G;Holmes MC;Gregory PD;Ando DG;Kalos M;Collman RG;Binder-Scholl G;Plesa G;Hwang WT;Levine BL;June CH
通讯作者：
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