Infectious clones and vectors derived from adeno-associated virus (AAV) serotypes other than AAV type 2
Infectious clones and vectors derived from adeno-associated virus (AAV) serotypes other than AAV type 2
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DOI：
10.1128/jvi.72.1.309-319.1998
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发表时间：
1998-01-01
影响因子：
5.4
通讯作者：
Russell, DW
中科院分区：
文献类型：
--
作者：
Rutledge, EA;Halbert, CL;Russell, DW
腺相关病毒（aav）是一种单链依赖性细小病毒，正在被开发为转导载体。虽然存在至少5种血清型（AAV 1 ~ 5型[AAV1 ~ -5]），但仅对AAV2、AAV3和AAV4进行了测序，且使用的载体几乎全部来源于AAV2。在这里，我们报道了AAV3第二个基因组的克隆和测序，以及与AAV1相关的新的AAV6血清型。在核苷酸序列水平上，AAV2、AAV3和AAV6具有82%的同源性，AAV4与这些AAV2、AAV3和AAV6具有75% ~ 78%的同源性。在可能负责血清型特异性功能的衣壳蛋白部分中发现了显著的序列变异。由AAV3和AAV6产生的载体在宿主范围和血清学反应性上与AAV2载体不同，AAV3和AAV6载体血清型能够在先前暴露于AAV2载体的动物血清存在的情况下转导细胞。我们的研究结果表明，基于其他AAV血清型的载体将比现有的AAV2载体具有优势，包括不同细胞类型的转导，以及对AAV2中和抗体的抗性。这对于基因治疗尤其重要，因为人类对AAV2存在显著的免疫力，许多方案可能需要多次载体剂量。
Adeno-associated viruses (AAVs) are single-stranded dependent parvoviruses being developed as transducing vectors. Although at least five serotypes exist (AAV types 1 to 5 [AAV1 to -5]), only AAV2, AAV3, and AAV4 have been sequenced, and the vectors in use were almost all derived from AAV2. Here we report the cloning and sequencing of a second AAV3 genome and a new AAV serotype designated AAV6 that is related to AAV1. AAV2, AAV3, and AAV6 were 82% identical at the nucleotide sequence level, and AAV4 was 75 to 78% identical to these AAVs. Significant sequence variation was noted in portions of the capsid proteins that presumably are responsible for serotype-specific functions. Vectors produced from AAV3 and AAV6 differed from AAV2 vectors in host range and serologic reactivity, The AAV3 and AAV6 vector serotypes were able to transduce cells in the presence of serum from animals previously exposed to AAV2 vectors. Our results suggest that vectors based on alternative AAV serotypes will have advantages over existing AAV2 vectors, including the transduction of different cell types, and resistance to neutralizing antibodies against AAV2. This could be especially important for gene therapy, as significant immunity against AAV2 exists in human populations and many protocols will likely require multiple vector doses.