Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, NY.
Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital and Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
Hepatology. 2021 Sep;74(3):1148-1163. doi: 10.1002/hep.31802. Epub 2021 Jun 11.
Equine hepacivirus (EqHV) is phylogenetically the closest relative of HCV and shares genome organization, hepatotropism, transient or persistent infection outcome, and the ability to cause hepatitis. Thus, EqHV studies are important to understand equine liver disease and further as an outbred surrogate animal model for HCV pathogenesis and protective immune responses. Here, we aimed to characterize the course of EqHV infection and associated protective immune responses.
Seven horses were experimentally inoculated with EqHV, monitored for 6 months, and rechallenged with the same and, subsequently, a heterologous EqHV. Clearance was the primary outcome (6 of 7) and was associated with subclinical hepatitis characterized by lymphocytic infiltrate and individual hepatocyte necrosis. Seroconversion was delayed and antibody titers waned slowly. Clearance of primary infection conferred nonsterilizing immunity, resulting in shortened duration of viremia after rechallenge. Peripheral blood mononuclear cell responses in horses were minimal, although EqHV-specific T cells were identified. Additionally, an interferon-stimulated gene signature was detected in the liver during EqHV infection, similar to acute HCV in humans. EqHV, as HCV, is stimulated by direct binding of the liver-specific microRNA (miR), miR-122. Interestingly, we found that EqHV infection sequesters enough miR-122 to functionally affect gene regulation in the liver. This RNA-based mechanism thus could have consequences for pathology.
EqHV infection in horses typically has an acute resolving course, and the protective immune response lasts for at least a year and broadly attenuates subsequent infections. This could have important implications to achieve the primary goal of an HCV vaccine; to prevent chronicity while accepting acute resolving infection after virus exposure.
马乙型肝炎病毒（EqHV）在系统发生上与 HCV 最为接近，具有基因组结构、嗜肝性、短暂或持续感染结果以及引起肝炎的能力。因此，EqHV 的研究对于了解马肝脏疾病以及作为 HCV 发病机制和保护性免疫反应的异源替代动物模型都很重要。在此，我们旨在描述 EqHV 感染的过程和相关的保护性免疫反应。
7 匹马被实验性接种 EqHV，监测 6 个月，并对相同的 EqHV 以及随后的异源 EqHV 进行再挑战。清除是主要结果（7 匹马中的 6 匹），并与亚临床肝炎相关，其特征为淋巴细胞浸润和个别肝细胞坏死。血清转换延迟，抗体滴度缓慢下降。原发性感染的清除赋予非无菌性免疫，导致再挑战后病毒血症持续时间缩短。尽管鉴定了 EqHV 特异性 T 细胞，但马的外周血单核细胞反应很小。此外，在 EqHV 感染期间在肝脏中检测到干扰素刺激基因特征，与人类急性 HCV 相似。EqHV 与 HCV 一样，通过肝脏特异性 microRNA（miR）miR-122 的直接结合而受到刺激。有趣的是，我们发现 EqHV 感染会隔离足够的 miR-122 以在肝脏中对基因调控产生功能性影响。这种基于 RNA 的机制因此可能对病理学产生影响。
马的 EqHV 感染通常具有急性缓解过程，而保护性免疫反应至少持续一年，并广泛减轻随后的感染。这对于实现 HCV 疫苗的主要目标可能具有重要意义；即在病毒暴露后接受急性缓解感染的同时，防止慢性化。
