Gregori Josep, Colomer-Castell Sergi, Ibañez-Lligoña Marta, Garcia-Cehic Damir, Campos Carolina, Buti Maria, Riveiro-Barciela Mar, Andrés Cristina, Piñana Maria, González-Sánchez Alejandra, Rodriguez-Frias Francisco, Cortese Maria Francesca, Tabernero David, Rando-Segura Ariadna, Pumarola Tomás, Esteban Juan Ignacio, Antón Andrés, Quer Josep
Liver Diseases-Viral Hepatitis, Liver Unit, Vall d'Hebron Institut of Research (VHIR), Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5, 28029 Madrid, Spain.
Microorganisms. 2024 May 17;12(5):1011. doi: 10.3390/microorganisms12051011.
The repeated failure to treat patients chronically infected with hepatitis E (HEV) and C (HCV) viruses, despite the absence of resistance-associated substitutions (RAS), particularly in response to prolonged treatments with the mutagenic agents of HEV, suggests that quasispecies structure may play a crucial role beyond single point mutations. Quasispecies structured in a flat-like manner (referred to as flat-like) are considered to possess high average fitness, occupy a significant fraction of the functional genetic space of the virus, and exhibit a high capacity to evade specific or mutagenic treatments. In this paper, we studied HEV and HCV samples using high-depth next-generation sequencing (NGS), with indices scoring the different properties describing flat-like quasispecies. The significance of these indices was demonstrated by comparing the values obtained from these samples with those from acute infections caused by respiratory viruses (betacoronaviruses, enterovirus, respiratory syncytial viruses, and metapneumovirus). Our results revealed that flat-like quasispecies in HEV and HCV chronic infections without RAS are characterized by numerous low-frequency haplotypes with no dominant one. Surprisingly, these low-frequency haplotypes (at the nucleotide level) exhibited a high level of synonymity, resulting in much lower diversity at the phenotypic level. Currently, clinical approaches for managing flat-like quasispecies are lacking. Here, we propose methods to identifying flat-like quasispecies, which represents an essential initial step towards exploring alternative treatment protocols for viruses resistant to conventional therapies.
尽管不存在与耐药相关的替代突变（RAS），但对于慢性感染戊型肝炎病毒（HEV）和丙型肝炎病毒（HCV）的患者，反复治疗失败，尤其是在使用HEV诱变剂进行长期治疗时，这表明准种结构可能在单点突变之外发挥关键作用。以扁平状方式构建的准种（称为扁平状准种）被认为具有较高的平均适应性，占据病毒功能遗传空间的很大一部分，并表现出较高的逃避特定或诱变治疗的能力。在本文中，我们使用高深度下一代测序（NGS）研究了HEV和HCV样本，并使用指标对描述扁平状准种的不同特性进行评分。通过将这些样本获得的值与由呼吸道病毒（β冠状病毒、肠道病毒、呼吸道合胞病毒和偏肺病毒）引起的急性感染样本的值进行比较，证明了这些指标的重要性。我们的结果表明，在没有RAS的HEV和HCV慢性感染中，扁平状准种的特征是存在大量低频单倍型，没有优势单倍型。令人惊讶的是，这些低频单倍型（在核苷酸水平）表现出高度的同义性，导致在表型水平上的多样性低得多。目前，缺乏管理扁平状准种的临床方法。在此，我们提出了识别扁平状准种的方法，这是探索针对传统疗法耐药病毒的替代治疗方案的重要第一步。
