Bailey Jacob T, Cangialosi Sophia, Moshkani Safiehkhatoon, Rexhouse Catherine, Cimino Jesse L, Robek Michael D
Department of Immunology & Microbial Disease, Albany Medical College, Albany, NY 12208, USA.
JHEP Rep. 2024 May 21;6(9):101121. doi: 10.1016/j.jhepr.2024.101121. eCollection 2024 Sep.
BACKGROUND & AIMS: HBV treatment is challenging due to the persistence of the covalently closed circular DNA replication pool, which remains unaffected by antiviral intervention. In this study, we determined whether targeting antigen-presenting cells via CD40 stimulation represents an appropriate therapeutic approach for achieving sustained HBV control in a mouse model of HBV replication.
Mice were transduced with an adeno-associated virus encoding the HBV genome (AAV-HBV) to initiate HBV replication and were administered agonistic CD40 antibody. CD4-depleting antibody was administered in addition to the CD40 antibody. Viral antigens in the blood were measured over time to determine HBV control. HBV-specific CD8 T cells were quantified in the spleen and liver at the experimental endpoint.
CD40 stimulation in CD4-depleted AAV-HBV mice resulted in the clearance of HBsAg and HBeAg, along with a reduction in liver HBV mRNA, contrasting with CD4-competent counterparts. CD8 T cells were indispensable for CD40-mediated HBV control, determined by HBV persistence following their depletion. In CD4-replete mice, CD40 stimulation initially facilitated the expansion of HBV-specific CD8 T cells, which subsequently could not control HBV. Finally, α-CD4/CD40 treatment reduced antigenemia and liver HBV mRNA levels in chronic AAV-HBV mice, with further enhancement through synergy with immunization by VSV-MHBs (vesicular stomatitis virus expressing middle HBsAg).
Our findings underscore the potential of CD40 stimulation as a targeted therapeutic strategy for achieving sustained HBV control and reveal a CD4 T cell-dependent limitation on CD40-mediated antiviral efficacy.
Immunotherapy has the potential to overcome immune dysfunction in chronic HBV infection. Using a mouse model of HBV replication, this study shows that CD40 stimulation can induce sustained HBV control, which is dependent on CD8 T cells and further enhanced by co-immunization. Unexpectedly, CD40-mediated HBV reduction was improved by the depletion of CD4 cells. These findings suggest potential strategies for reversing HBV persistence in infected individuals.
由于共价闭合环状DNA复制池持续存在，乙肝病毒（HBV）治疗颇具挑战性，该复制池不受抗病毒干预影响。在本研究中，我们确定通过CD40刺激靶向抗原呈递细胞是否代表一种在HBV复制小鼠模型中实现持续HBV控制的合适治疗方法。
用编码HBV基因组的腺相关病毒（AAV-HBV）转导小鼠以启动HBV复制，并给予激动性CD40抗体。除CD40抗体外，还给予CD4耗竭抗体。随时间测量血液中的病毒抗原以确定HBV控制情况。在实验终点对脾脏和肝脏中的HBV特异性CD8 T细胞进行定量。
在CD4耗竭的AAV-HBV小鼠中，CD40刺激导致HBsAg和HBeAg清除，同时肝脏HBV mRNA减少，这与具有CD4功能的对应小鼠形成对比。通过CD8 T细胞耗竭后HBV的持续存在确定，CD8 T细胞对于CD40介导的HBV控制不可或缺。在CD4充足的小鼠中，CD40刺激最初促进了HBV特异性CD8 T细胞的扩增，但其随后无法控制HBV。最后，α-CD4/CD40治疗降低了慢性AAV-HBV小鼠的抗原血症和肝脏HBV mRNA水平，通过与VSV-MHBs（表达中HBsAg的水泡性口炎病毒）免疫协同作用进一步增强。
我们的研究结果强调了CD40刺激作为实现持续HBV控制的靶向治疗策略的潜力，并揭示了CD4 T细胞依赖性对CD40介导的抗病毒疗效的限制。
免疫疗法有潜力克服慢性HBV感染中的免疫功能障碍。使用HBV复制小鼠模型，本研究表明CD40刺激可诱导持续的HBV控制，这依赖于CD8 T细胞并通过联合免疫进一步增强。出乎意料的是，CD4细胞的耗竭改善了CD40介导的HBV减少。这些发现提示了在感染个体中逆转HBV持续存在的潜在策略。
