Adeno-Associated Virus-Mediated Gene Transfer Leads to Persistent Hepatitis B Virus Replication in Mice Expressing HLA-A2 and HLA-DR1 Molecules
Adeno-Associated Virus-Mediated Gene Transfer Leads to Persistent Hepatitis B Virus Replication in Mice Expressing HLA-A2 and HLA-DR1 Molecules
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DOI：
10.1128/jvi.03134-12
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发表时间：
2013-05-01
影响因子：
5.4
通讯作者：
Michel, Marie-Louise
中科院分区：
文献类型：
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作者：
Dion, Sarah;Bourgine, Maryline;Michel, Marie-Louise
B型肝炎病毒（HBV）的持续存在可能是由于受损的HBV特异性免疫应答不能有效消除或治愈受感染的肝细胞。导致HBV持续存在的免疫机制尚未完全确定，也没有合适的动物模型可用于此类研究。因此，我们建立了一个慢性HBV感染模型的小鼠株与人类白细胞抗原A2/DR 1（HLA-A2/DR 1）转基因和H-2类I/II类基因敲除。这些小鼠的肝脏用携带有复制能力的HBV DNA基因组的腺相关病毒血清型2/8（AAV 2/8）转导。在所有AAV 2/8转导的小鼠中，B型肝炎病毒表面抗原、B型肝炎病毒e抗原和HBV DNA在血清中持续存在至少1年。在注射AAV的小鼠的肝脏中检测到病毒复制中间体和转录物。B型肝炎核心抗原在60%的肝细胞中表达。在肝脏中未观察到显著炎症。这与肝脏中调节性T细胞的数量高于对照组和HBV特异性功能性T细胞应答的缺陷有关。尽管在肝细胞中表达HBV抗原导致了大量的耐受性，但我们成功地在外周组织中引发了功能性HBV特异性T细胞应答，随后到达肝脏。这种AAV 2/8-HBV转导的HLA-A2/DR 1小鼠模型概括了慢性HBV感染的病毒学和免疫学特征，并且它可能用于开发用于慢性HBV感染的新治疗和基于免疫的治疗或治疗性疫苗。
Hepatitis B virus (HBV) persistence may be due to impaired HBV-specific immune responses being unable to eliminate efficiently or cure infected hepatocytes. The immune mechanisms that lead to HBV persistence have not been completely identified, and no appropriate animal model is available for such studies. Therefore, we established a chronic HBV infection model in a mouse strain with human leukocyte antigen A2/DR1 (HLA-A2/DR1) transgenes and an H-2 class I/class II knockout. The liver of these mice was transduced with adeno-associated virus serotype 2/8 (AAV2/8) carrying a replication-competent HBV DNA genome. In all AAV2/8-transduced mice, hepatitis B virus surface antigen, hepatitis B virus e antigen, and HBV DNA persisted in serum for at least 1 year. Viral replication intermediates and transcripts were detected in the livers of the AAV-injected mice. The hepatitis B core antigen was expressed in 60% of hepatocytes. No significant inflammation was observed in the liver. This was linked to a higher number of regulatory T cells in liver than in controls and a defect in HBV-specific functional T-cell responses. Despite the substantial tolerance resulting from expression of HBV antigens in hepatocytes, we succeeded in priming functional HBV-specific T-cell responses in peripheral tissues, which subsequently reached the liver. This AAV2/8-HBV-transduced HLA-A2/DR1 murine model recapitulates virological and immunological characteristics of chronic HBV infection, and it could be useful for the development of new treatments and immune-based therapies or therapeutic vaccines for chronic HBV infections.