CD8+ T cell recognition of epitopes within the capsid of adeno-associated virus 8-based gene transfer vectors depends on vectors' genome.
CD8+ T cell recognition of epitopes within the capsid of adeno-associated virus 8-based gene transfer vectors depends on vectors' genome.
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DOI：
10.1038/mt.2013.218
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发表时间：
2014
期刊：
影响因子：
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通讯作者：
Te-Lang Wu;Hua Li;Susan M. Faust;Emily Chi;Shangzhen Zhou;Fraser Wright;K. High;H. Ertl
中科院分区：
文献类型：
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作者：
Te-Lang Wu;Hua Li;Susan M. Faust;Emily Chi;Shangzhen Zhou;Fraser Wright;K. High;H. Ertl
表达人因子IX（hF.IX）的自身互补腺相关病毒（AAV）载体已经在人类志愿者中实现了血友病B的短暂或持续校正。递送至肝脏的高剂量的AAV 2或AAV 8载体在几个患者中引起转氨酶增加，伴随着AAV衣壳蛋白特异性T细胞的上升和循环hF.IX水平的降低，表明载体转导的细胞的免疫介导的破坏。这些不良事件的动力学在接受AAV2或AAV8载体的患者中不同，分别在载体注射后3周和8周引起转氨酶升高。为了测试CD8+T细胞与AAV8载体（其与AAV2载体类似，是完全被掏空的载体，因此不能编码结构病毒蛋白）是否可以在这个晚期时间点引起损伤，我们在一系列小鼠研究中测试了AAV8衣壳内的主要组织相容性（MHC）I类表位可以呈递给CD8+T细胞多长时间。我们的结果清楚地表明，根据载体的基因组，CD8+T细胞可以检测AAV8衣壳上的此类表位长达6个月，表明AAV8的衣壳在小鼠中缓慢降解。
Self-complementary adeno-associated viral (AAV) vectors expressing human factor IX (hF.IX) have achieved transient or sustained correction of hemophilia B in human volunteers. High doses of AAV2 or AAV8 vectors delivered to the liver caused in several patients an increase in transaminases accompanied by a rise in AAV capsid-specific T cells and a decrease in circulating hF.IX levels suggesting immune-mediated destruction of vector-transduced cells. Kinetics of these adverse events differed in patients receiving AAV2 or AAV8 vectors causing rise in transaminases at 3 versus 8 weeks after vector injection, respectively. To test if CD8+T cells to AAV8 vectors, which are similar to AAV2 vectors are fully-gutted vectors and thereby fail to encode structural viral proteins, could cause damage at this late time point, we tested in a series of mouse studies how long major histocompatibility (MHC) class I epitopes within AAV8 capsid can be presented to CD8+T cells. Our results clearly show that depending on the vectors' genome, CD8+T cells can detect such epitopes on AAV8's capsid for up to 6 months indicating that the capsid of AAV8 degrades slowly in mice.