Immune effectors required for hepatitis B virus clearance
Immune effectors required for hepatitis B virus clearance
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DOI：
10.1073/pnas.0913498107
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发表时间：
2010-01-12
影响因子：
11.1
通讯作者：
Chisari, Francis V.
中科院分区：
文献类型：
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作者：
Yang, Priscilla L.;Althage, Alana;Chisari, Francis V.
为了更好地确定可能负责B型肝炎病毒（HBV）感染期间病毒清除的机制，在一组免疫缺陷小鼠品系中研究了病毒清除，这些小鼠品系用含有HBV基因组复制能力拷贝的质粒进行水动力转染。从肝脏清除病毒DNA转录模板既不需要B细胞也不需要穿孔素。相比之下，模板在NOD/Scid小鼠中以高水平持续至少60天，在不存在CD 4（+）和CD 8（+）T细胞、NK细胞、Fas、IFN-γ（IFN-γ）、IFN-α/β受体（IFN-α/β R1）和TNF受体1（TNFR 1）的情况下以较低水平持续至少60天，表明这些效应子中的每一个都是从肝脏中消除转录模板所必需的。有趣的是，除了NOD/Scid小鼠之外，所有谱系的病毒复制最终都被终止，这表明存在抑制HBV复制的冗余途径。最后，在这些动物中诱导CD 8（+）T细胞应答取决于CD 4（+）T细胞的存在。这些结果与CD 4（+）T细胞作为HBV适应性免疫应答的主要调节者的模型一致; CD 8（+）T细胞是介导HBV从肝脏清除的关键细胞效应物，显然是通过Fas依赖性、穿孔素非依赖性过程，其中NK细胞、IFN-γ、TNFR 1和IFN-α/β R起支持作用。这些结果提供了深入了解HBV清除所涉及的系统的复杂性，并为分析HBV持续存在的机制提供了独特的方向。
To better define the mechanism(s) likely responsible for viral clearance during hepatitis B virus (HBV) infection, viral clearance was studied in a panel of immunodeficient mouse strains that were hydrodynamically transfected with a plasmid containing a replication-competent copy of the HBV genome. Neither B cells nor perforin were required to clear the viral DNA transcriptional template from the liver. In contrast, the template persisted for at least 60 days at high levels in NOD/Scid mice and at lower levels in the absence of CD4(+) and CD8(+) T cells, NK cells, Fas, IFN-gamma (IFN-gamma), IFN-alpha/beta receptor (IFN-alpha/beta R1), and TNF receptor 1 (TNFR1), indicating that each of these effectors was required to eliminate the transcriptional template from the liver. Interestingly, viral replication was ultimately terminated in all lineages except the NOD/Scid mice, suggesting the existence of redundant pathways that inhibit HBV replication. Finally, induction of a CD8(+) T cell response in these animals depended on the presence of CD4(+) T cells. These results are consistent with a model in which CD4(+) T cells serve as master regulators of the adaptive immune response to HBV; CD8(+) T cells are the key cellular effectors mediating HBV clearance from the liver, apparently by a Fas-dependent, perforin-independent process in which NK cells, IFN-gamma, TNFR1, and IFN-alpha/beta R play supporting roles. These results provide insight into the complexity of the systems involved in HBV clearance, and they suggest unique directions for analysis of the mechanism(s) responsible for HBV persistence.