Zaiss Anne K, Muruve Daniel A
Department of Biochemistry & Molecular Biology, University of Calgary, 3330 Hospital Drive N.W., Calgary, Alberta T2N 4N1, Canada.
Curr Gene Ther. 2005 Jun;5(3):323-31. doi: 10.2174/1566523054065039.
One of the biggest challenges in optimizing viral vectors for gene therapy relates to the immune response of the host. Adeno-associated virus (AAV) vectors are associated with low immunogenicity and toxicity, resulting in vector persistence and long-term transgene expression. The inability of AAV vectors to efficiently transduce or activate antigen presenting cells (APCs) may account for their decreased immunogenicity. AAV mediated gene therapy however, leads to the development of antibodies against the vector capsid. Anti-AAV antibodies have neutralizing effects that decrease the efficiency of in vivo gene therapy and can prevent vector re-administration. Furthermore, recent studies have shown that AAV vectors can elicit both cellular and humoral immune responses against the transgene product. Both cell-mediated response and humoral response to the delivered gene depend on a number of variables; including the nature of the transgene, the promoter used, the route and site of administration, vector dose and host factors. The response of the host to the vector, in terms of antigen-specific immunity, will play a substantial role in clinical outcome. It is therefore important to understand both, why AAV vectors are able to escape immunity and the circumstances and mechanisms that lead to the induction of immune responses. This review will summarize innate and adaptive immune responses to AAV vectors, discuss possible mechanisms and outline strategies, such as capsid modifications, use of alternative serotypes, or immunosuppression, which have been used to circumvent them.
优化用于基因治疗的病毒载体面临的最大挑战之一与宿主的免疫反应有关。腺相关病毒（AAV）载体具有低免疫原性和低毒性，可使载体持续存在并实现转基因的长期表达。AAV载体无法有效转导或激活抗原呈递细胞（APC）可能是其免疫原性降低的原因。然而，AAV介导的基因治疗会导致针对载体衣壳的抗体产生。抗AAV抗体具有中和作用，会降低体内基因治疗的效率，并可能阻止载体再次给药。此外，最近的研究表明，AAV载体可引发针对转基因产物的细胞免疫和体液免疫反应。对所递送基因的细胞介导反应和体液反应取决于多个变量，包括转基因的性质、所用启动子、给药途径和部位、载体剂量以及宿主因素。宿主对载体的反应，就抗原特异性免疫而言，将在临床结果中发挥重要作用。因此，了解AAV载体为何能够逃避免疫以及导致免疫反应诱导的情况和机制都很重要。本综述将总结对AAV载体的固有免疫和适应性免疫反应，讨论可能的机制，并概述已用于规避这些反应的策略，如衣壳修饰、使用替代血清型或免疫抑制。
