Pichard Virginie, Guilbaud Mickaël, Devaux Marie, Jaulin Nicolas, Journou Malo, Cospolite Magalie, Garcia Alexandra, Ferry Nicolas, Michalak-Provost Sophie, Gernoux Gwladys, Adjali Oumeya
Nantes Université, CHU Nantes, INSERM, TaRGeT-Translational Research in Gene Therapy, UMR1089, F-44200, Nantes, France.
CHU Nantes, Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, F-44000, Nantes, France.
Gene Ther. 2025 Jan 21. doi: 10.1038/s41434-025-00514-z.
The liver is a unique organ where immunity can be biased toward ineffective response notably in the context of viral infections. Chronic viral hepatitis depends on the inability of the T-cell immune response to eradicate antigen. In the case of recombinant Adeno-Associated-Virus, used for therapeutic gene transfer, conflicting reports describe tolerance induction to different transgene products while other studies have shown conventional cytotoxic CD8 T cell responses with a rapid loss of transgene expression. We performed a 1 year follow up of 6 non-human primates after all animals received an rAAV8 vector carrying the GFP transgene at doses of 7×10 vg/kg. We report that despite anti-GFP peripheral cellular response and loss of hepatic transgene expression, we were still able to detect persisting viral genomes in the liver until 1-year post-injection. These viral genomes were associated with liver inflammation, fibrosis and signs of CD8 T cell exhaustion, including high expression of PD-1. Our study shows that AAV8-mediated gene transfer can results to loss of transgene expression in liver and chronic inflammation several months after gene transfer.
肝脏是一个独特的器官，在病毒感染的情况下，其免疫反应可能偏向于无效反应。慢性病毒性肝炎取决于T细胞免疫反应无法清除抗原。在用于治疗性基因转移的重组腺相关病毒（rAAV）的情况下，相互矛盾的报告描述了对不同转基因产物的耐受性诱导，而其他研究则显示了传统的细胞毒性CD8 T细胞反应以及转基因表达的快速丧失。在所有动物接受剂量为7×10 vg/kg携带绿色荧光蛋白（GFP）转基因的rAAV8载体后，我们对6只非人灵长类动物进行了为期1年的随访。我们报告称，尽管存在抗GFP外周细胞反应以及肝脏转基因表达丧失，但在注射后1年，我们仍能够在肝脏中检测到持续存在的病毒基因组。这些病毒基因组与肝脏炎症、纤维化以及CD8 T细胞耗竭的迹象有关，包括程序性死亡受体1（PD-1）的高表达。我们的研究表明，AAV8介导的基因转移可导致基因转移数月后肝脏中转基因表达丧失和慢性炎症。
