Gene therapy with adeno-associated virus (AAV) vectors has demonstrated safety and long-term efficacy in a number of trials across target organs, including eye, liver, skeletal muscle, and the central nervous system. Since the initial evidence that AAV vectors can elicit capsid T cell responses in humans, which can affect the duration of transgene expression, much progress has been made in understanding and modulating AAV vector immunogenicity. It is now well established that exposure to wild-type AAV results in priming of the immune system against the virus, with development of both humoral and T cell immunity. Aside from the neutralizing effect of antibodies, the impact of pre-existing immunity to AAV on gene transfer is still poorly understood. Herein, we review data emerging from clinical trials across a broad range of gene therapy applications. Common features of immune responses to AAV can be found, suggesting, for example, that vector immunogenicity is dose-dependent, and that innate immunity plays an important role in the outcome of gene transfer. A range of host-specific factors are also likely to be important, and a comprehensive understanding of the mechanisms driving AAV vector immunogenicity in humans will be key to unlocking the full potential of in vivo gene therapy.

中文翻译：

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AAV 载体在人类中的免疫原性：成功基因转移的漫长旅程。

腺相关病毒 (AAV) 载体的基因治疗已在多个靶器官（包括眼、肝脏、骨骼肌和中枢神经系统）试验中证明了安全性和长期疗效。自从初步证据表明 AAV 载体可以在人体中引发衣壳 T 细胞反应，从而影响转基因表达的持续时间，在理解和调节 AAV 载体免疫原性方面已经取得了很大进展。现在已经确定，暴露于野生型 AAV 会导致免疫系统针对病毒的启动，并产生体液免疫和 T 细胞免疫。除了抗体的中和作用外，预先存在的 AAV 免疫对基因转移的影响仍然知之甚少。在此，我们回顾了广泛的基因治疗应用的临床试验中出现的数据。可以发现针对 AAV 的免疫反应的共同特征，这表明载体免疫原性是剂量依赖性的，并且先天免疫在基因转移的结果中起着重要作用。一系列宿主特异性因素也可能很重要，全面了解驱动人类 AAV 载体免疫原性的机制将是释放体内基因治疗全部潜力的关键。