Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital - Amager and Hvidovre, Copenhagen, Denmark.
Copenhagen Hepatitis C Program (CO-HEP), Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
Curr Top Microbiol Immunol. 2023;439:237-264. doi: 10.1007/978-3-031-15640-3_7.
Chronic infection with hepatitis C virus (HCV) is an important contributor to the global incidence of liver diseases, including liver cirrhosis and hepatocellular carcinoma. Although common for single-stranded RNA viruses, HCV displays a remarkable high level of genetic diversity, produced primarily by the error-prone viral polymerase and host immune pressure. The high genetic heterogeneity of HCV has led to the evolution of several distinct genotypes and subtypes, with important consequences for pathogenesis, and clinical outcomes. Genetic variability constitutes an evasion mechanism against immune suppression, allowing the virus to evolve epitope escape mutants that avoid immune recognition. Thus, heterogeneity and variability of the HCV genome represent a great hindrance for the development of vaccines against HCV. In addition, the high genetic plasticity of HCV allows the virus to rapidly develop antiviral resistance mutations, leading to treatment failure and potentially representing a major hindrance for the cure of chronic HCV patients. In this chapter, we will present the central role that genetic diversity has in the viral life cycle and epidemiology of HCV. Incorporation errors and recombination, both the result of HCV polymerase activity, represent the main mechanisms of HCV evolution. The molecular details of both mechanisms have been only partially clarified and will be presented in the following sections. Finally, we will discuss the major consequences of HCV genetic diversity, namely its capacity to rapidly evolve antiviral and immunological escape variants that represent an important limitation for clearance of acute HCV, for treatment of chronic hepatitis C and for broadly protective vaccines.
慢性丙型肝炎病毒（HCV）感染是导致全球肝脏疾病（包括肝硬化和肝细胞癌）发病率的重要因素。尽管单链 RNA 病毒很常见，但 HCV 表现出显著的高水平遗传多样性，主要由易错的病毒聚合酶和宿主免疫压力产生。HCV 的高度遗传异质性导致了几种不同基因型和亚型的进化，对发病机制和临床结果有重要影响。遗传变异构成了对免疫抑制的逃避机制，使病毒能够进化出逃避免疫识别的表位逃逸突变体。因此，HCV 基因组的异质性和可变性是开发 HCV 疫苗的一大障碍。此外，HCV 的高遗传可塑性允许病毒迅速产生抗病毒耐药突变，导致治疗失败，并可能成为慢性 HCV 患者治愈的主要障碍。在本章中，我们将介绍遗传多样性在 HCV 病毒生命周期和流行病学中的核心作用。整合错误和重组，都是 HCV 聚合酶活性的结果，是 HCV 进化的主要机制。这两种机制的分子细节仅部分阐明，并将在以下部分介绍。最后，我们将讨论 HCV 遗传多样性的主要后果，即其迅速进化出抗病毒和免疫逃逸变异体的能力，这对清除急性 HCV、治疗慢性丙型肝炎和广泛保护性疫苗具有重要限制。
