Hepacivirus A Infection in Horses Defines Distinct Envelope Hypervariable Regions and Elucidates Potential Roles of Viral Strain and Adaptive Immune Status in Determining Envelope Diversity and Infection Outcome.
Hepacivirus A Infection in Horses Defines Distinct Envelope Hypervariable Regions and Elucidates Potential Roles of Viral Strain and Adaptive Immune Status in Determining Envelope Diversity and Infection Outcome.
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马的 A 型肝炎病毒感染定义了独特的包膜高变区，并阐明了病毒株和适应性免疫状态在确定包膜多样性和感染结果中的潜在作用。
DOI：
10.1128/jvi.00314-18
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发表时间：
2018
影响因子：
5.4
通讯作者：
Mealey,RobertH
中科院分区：
文献类型：
--
作者：
Ramsay,JoshuaD;Evanoff,Ryan;Mealey,RobertH
A型肝炎病毒（也称为非灵长类肝炎病毒和马肝炎病毒）是一种嗜肝病毒，可引起马的一过性和持续性感染。尚未详细研究A型肝炎病毒宿主内病毒种群（准种）的进化，其在免疫逃避和持久性中的作用尚不清楚。为了解决这些知识的差距，我们首先评估了包膜基因（E1和E2）的多样性，两种不同的A型肝炎病毒株（WSU和CU）的纵向血液样本从实验感染的成年马，幼年马（马驹），马驹与严重联合免疫缺陷（SCID）。与自发清除感染的马（P= 0.0002）或SCID马驹（P< 0.0001）相比，WSU菌株的持续感染与显著更大的准种多样性相关。相比之下，CU菌株能够持续存在，尽管显著较低（P< 0.0001）和相对静态的信封多样性。这些发现表明，包膜多样性是一个贫穷的预测肝炎病毒A感染的结果，并可能依赖于株特异性因素。然后对GenBank中的所有E1/E2基因进行熵分析。该分析在E2中定义了三个新的高变区（HVR），在残基391至402（HVR 1）、450至461（HVR 2）和550至562（HVR 3）处。对于实验感染的马，熵分析集中在HVR表明，这些地区在持续感染的选择压力增加。HVR多样性的增加也与一些马的血清转化存在时间相关性，这表明这些区域可能是中和抗体的靶点，并可能在免疫逃避中发挥作用。重要提示丙型肝炎病毒（丙型肝炎病毒）估计感染全球1.5亿人，是肝硬化和肝细胞癌的主要原因。相比之下，其最近的亲戚，肝炎病毒A，导致相对温和的疾病，在马和经常被清除。关于A型肝炎病毒的准种进化和感染结果之间的关系尚未研究。为了解决这一知识差距，我们研究了解决和持续感染的马的包膜基因多样性。有趣的是，出现了两个应变特定模式的准种多样性。持久性的WSU菌株与准种多样性增加和积累的氨基酸变化在三个新的高变区血清转换后。这些发现提供了证据，包膜基因突变的影响，适应性免疫压力，并可能有助于肝炎病毒的持久性。然而，CU株持续存在，尽管相对进化停滞，这表明一些肝炎病毒株可能使用替代机制在宿主中持续存在。
Hepacivirus A (also known as nonprimate hepacivirus and equine hepacivirus) is a hepatotropic virus that can cause both transient and persistent infections in horses. The evolution of intrahost viral populations (quasispecies) has not been studied in detail for hepacivirus A, and its roles in immune evasion and persistence are unknown. To address these knowledge gaps, we first evaluated the envelope gene (E1 and E2) diversity of two different hepacivirus A strains (WSU and CU) in longitudinal blood samples from experimentally infected adult horses, juvenile horses (foals), and foals with severe combined immunodeficiency (SCID). Persistent infection with the WSU strain was associated with significantly greater quasispecies diversity than that observed in horses who spontaneously cleared infection (P= 0.0002) or in SCID foals (P< 0.0001). In contrast, the CU strain was able to persist despite significantly lower (P< 0.0001) and relatively static envelope diversity. These findings indicate that envelope diversity is a poor predictor of hepacivirus A infection outcomes and could be dependent on strain-specific factors. Next, entropy analysis was performed on all E1/E2 genes entered into GenBank. This analysis defined three novel hypervariable regions (HVRs) in E2, at residues 391 to 402 (HVR1), 450 to 461 (HVR2), and 550 to 562 (HVR3). For the experimentally infected horses, entropy analysis focusing on the HVRs demonstrated that these regions were under increased selective pressure during persistent infection. Increased diversity in the HVRs was also temporally associated with seroconversion in some horses, suggesting that these regions may be targets of neutralizing antibody and may play a role in immune evasion.IMPORTANCEHepacivirus C (hepatitis C virus) is estimated to infect 150 million people worldwide and is a leading cause of cirrhosis and hepatocellular carcinoma. In contrast, its closest relative, hepacivirus A, causes relatively mild disease in horses and is frequently cleared. The relationship between quasispecies evolution and infection outcome has not been explored for hepacivirus A. To address this knowledge gap, we examined envelope gene diversity in horses with resolving and persistent infections. Interestingly, two strain-specific patterns of quasispecies diversity emerged. Persistence of the WSU strain was associated with increased quasispecies diversity and the accumulation of amino acid changes within three novel hypervariable regions following seroconversion. These findings provided evidence that envelope gene mutation is influenced by adaptive immune pressure and may contribute to hepacivirus persistence. However, the CU strain persisted despite relative evolutionary stasis, suggesting that some hepacivirus strains may use alternative mechanisms to persist in the host.