PDF(Pubmed)
Abstract：
Hepatitis B virus (HBV) has afflicted humankind for decades and there is still no treatment that can clear the infection. The development of recombinant adeno-associated virus (rAAV)-based gene therapy for HBV infection has become important in recent years and research has made exciting leaps. Initial studies, mainly using mouse models, showed that rAAVs are non-toxic and induce minimal immune responses. However, several later studies demonstrated rAAV toxicity, which is inextricably associated with immunogenicity. This is a major setback for the progression of rAAV-based therapies toward clinical application. Research aimed at understanding the mechanisms behind rAAV immunity and toxicity has contributed significantly to the inception of approaches to overcoming these challenges. The target tissue, the features of the vector, and the vector dose are some of the determinants of AAV toxicity, with the latter being associated with the most severe adverse events. This review discusses our current understanding of rAAV immunogenicity, toxicity, and approaches to overcoming these hurdles. How this information and current knowledge about HBV biology and immunity can be harnessed in the efforts to design safe and effective anti-HBV rAAVs is discussed.
摘要：
乙型肝炎病毒（HBV）几十年来一直困扰着人类，仍然没有可以清除感染的治疗方法。近年来，基于重组腺相关病毒（rAAV）的HBV感染基因治疗的发展变得很重要，并且研究取得了令人兴奋的飞跃。初步研究,主要使用鼠标模型，表明rAAV是无毒的并且诱导最小的免疫应答。然而,后来的几项研究证明了rAAV的毒性，这与免疫原性密不可分。这是基于rAAV的疗法向临床应用的进展的主要挫折。旨在了解rAAV免疫和毒性背后的机制的研究为克服这些挑战的方法的开始做出了重大贡献。目标组织，向量的特征，载体剂量是AAV毒性的一些决定因素，后者与最严重的不良事件有关。这篇综述讨论了我们目前对rAAV免疫原性的理解，毒性,以及克服这些障碍的方法。讨论了如何利用有关HBV生物学和免疫的信息和当前知识来设计安全有效的抗HBVrAAV。
