抗Toll样受体7激动剂GS-9620的抗HBV应答与T细胞和B细胞的肝内聚

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Anti-HBV Response to Toll-Like Receptor 7 Agonist GS-9620 is Associated with Intrahepatic Aggregates of T Cells and B Cells

Li Lia, Vivian Barry'Correspondence information about the author Vivian Barry, Stephane Daffis, Congrong Niu, Erik Huntzicker, Dorothy M. French, Igor Mikaelian, Robert E. Lanford, William E. Delaney IV, Simon P. Fletcher'Correspondence information about the author Simon P. FletcherEmail the author Simon P. Fletcher
DOI: http://dx.doi.org/10.1016/j.jhep.2017.12.008
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Highlights
•GS-9620 treatment induced the expression of genes associated with HBV clearance.
•GS-9620 treatment transiently induced intrahepatic lymphoid aggregates.
•The aggregates were not fully differentiated tertiary lymphoid structures.
•Intrahepatic NK cell number did not change during GS-9620 treatment.
Abstract
Background & Aims
GS-9620, an oral agonist of toll-like receptor 7 (TLR7), is in clinical development for the treatment of chronic hepatitis B (CHB). GS-9620 was previously shown to induced prolonged suppression of serum viral DNA and antigens in the chimpanzee and woodchuck models of CHB. Here we investigated the immunomodulatory mechanisms underlying these antiviral effects.

Methods
Archived liver biopsies and paired PBMC samples from a previous chimpanzee study were analyzed by RNA-Seq, qRT-PCR, immunohistochemistry (IHC) and in situ hybridization (ISH).

Results
GS-9620 treatment of CHB chimpanzees induced an intrahepatic transcriptional profile significantly enriched with genes associated with hepatitis B virus (HBV) clearance in acutely infected chimpanzees. Type I and II interferon, CD8+ T cell and B cell transcriptional signatures were associated with treatment response, together with evidence of hepatocyte death and liver regeneration. IHC and ISH confirmed an increase in intrahepatic CD8+ T cell and B cell numbers during treatment, and revealed that GS-9620 transiently induced aggregates predominantly comprised of CD8+ T cells and B cells in portal regions. There were no follicular dendritic cells (FDCs) or IgG-positive cells in these lymphoid aggregates and very few CD11b+ myeloid cells. There was no change in intrahepatic NK cell number during GS-9620 treatment.

Conclusion
The antiviral response to GS-9620 treatment in CHB chimpanzees was associated with an intrahepatic interferon response and formation of lymphoid aggregates in the liver. Our data indicate these intrahepatic structures are not fully differentiated follicles containing germinal center reactions. However, the temporal correlation between development of these T and B cell aggregates and the antiviral response to treatment suggests they play a role in promoting an effective immune response against HBV.

Lay summary
New therapies to treat chronic hepatitis B (CHB) are urgently needed. In this study we performed a retrospective analysis of liver and blood samples from a chimpanzee model of CHB to help understand how GS-9620, a drug in clinical trials, suppressed hepatitis B virus (HBV). We found that the antiviral response to GS-9620 was associated with accumulation of immune cells in the liver that can either kill cells infected with HBV or can produce antibodies that may prevent HBV from infecting new liver cells. These findings have important implications for how GS-9620 may be used in patients and may also help guide the development of new therapies to treat chronic HBV infection.

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抗Toll样受体7激动剂GS-9620的抗HBV应答与T细胞和B细胞的肝内聚集体有关

强调
•GS-9620治疗诱导了与HBV清除有关的基因的表达。
•GS-9620治疗暂时诱导肝内淋巴聚集。
•聚集体没有完全分化的第三级淋巴结构。
•在GS-9620治疗期间，肝内NK细胞数量没有变化。
抽象
背景和目的
Toll样受体7（TLR7）的口服激动剂GS-9620正在临床开发用于治疗慢性乙型肝炎（CHB）。先前显示GS-9620在CHB的黑猩猩和土拨鼠模型中诱导血清病毒DNA和抗原的长时间抑制。在这里，我们调查了这些抗病毒作用的免疫调节机制。

方法
通过RNA-Seq，qRT-PCR，免疫组织化学（IHC）和原位杂交（ISH）分析来自之前的黑猩猩研究的存档的肝活组织检查和配对的PBMC样品。

结果
慢性黑猩猩的GS-9620治疗诱导了在急性感染的黑猩猩中显着富集与乙型肝炎病毒（HBV）清除有关的基因的肝内转录谱。 I型和II型干扰素，CD8 + T细胞和B细胞转录特征与治疗应答相关，以及肝细胞死亡和肝再生的证据。 IHC和ISH证实治疗期间肝内CD8 + T细胞和B细胞数目增加，并且显示GS-9620瞬时诱导的聚集体主要由门静脉区中的CD8 + T细胞和B细胞组成。在这些淋巴聚集体中没有滤泡树突细胞（FDC）或IgG阳性细胞，并且很少CD11b +髓样细胞。在GS-9620处理期间，肝内NK细胞数量没有变化。

结论
在CHB黑猩猩中对GS-9620治疗的抗病毒应答与肝内干扰素应答和肝中淋巴聚集体的形成有关。我们的数据表明这些肝内结构不是完全分化的包含生发中心反应的卵泡。然而，这些T和B细胞聚集体的发展与对治疗的抗病毒反应之间的时间关系表明它们在促进针对HBV的有效免疫应答中发挥作用。

总结
迫切需要治疗慢性乙型肝炎（CHB）的新疗法。在这项研究中，我们对CHB黑猩猩模型的肝脏和血液样本进行了回顾性分析，以帮助理解临床试验中的GS-9620如何抑制乙型肝炎病毒（HBV）。我们发现对GS-9620的抗病毒反应与免疫细胞在肝脏中的积累有关，可以杀死感染HBV的细胞，或者可以产生可以阻止HBV感染新的肝细胞的抗体。这些发现对GS-9620如何用于患者有重要的意义，也有助于指导治疗慢性HBV感染的新疗法的发展。