Keck Mei-Le, Wrensch Florian, Pierce Brian G, Baumert Thomas F, Foung Steven K H
Department of Pathology, Stanford University School of Medicine, Stanford, CA, United States.
INSERM U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.
Front Immunol. 2018 May 31;9:1194. doi: 10.3389/fimmu.2018.01194. eCollection 2018.
Hepatitis C virus (HCV) continues to spread worldwide with an annual increase of 1.75 million new infections. The number of HCV cases in the U.S. is now greater than the number of HIV cases and is increasing in young adults because of the opioid epidemic sweeping the country. HCV-related liver disease is the leading indication of liver transplantation. An effective vaccine is of paramount importance to control and prevent HCV infection. While this vaccine will need to induce both cellular and humoral immunity, this review is focused on the required antibody responses. For highly variable viruses, such as HCV, isolation and characterization of monoclonal antibodies mediating broad virus neutralization are an important guide for vaccine design. The viral envelope glycoproteins, E1 and E2, are the main targets of these antibodies. Epitopes on the E2 protein have been studied more extensively than epitopes on E1, due to higher antibody targeting that reflects these epitopes having higher degrees of immunogenicity. E2 epitopes are overall organized in discrete clusters of overlapping epitopes that ranged from high conservation to high variability. Other epitopes on E1 and E1E2 also are targets of neutralizing antibodies. Taken together, these regions are important for vaccine design. Another element in vaccine design is based on information on how the virus escapes from broadly neutralizing antibodies. Escape mutations can occur within the epitopes that are involved in antibody binding and in regions that are not involved in their epitopes, but nonetheless reduce the efficiency of neutralizing antibodies. An understanding on the specificities of a protective B cell response, the molecular locations of these epitopes on E1, E2, and E1E2, and the mechanisms, which enable the virus to negatively modulate neutralizing antibody responses to these regions will provide the necessary guidance for vaccine design.
丙型肝炎病毒（HCV）继续在全球范围内传播，每年新增感染病例增加175万。美国的HCV病例数现已超过HIV病例数，并且由于席卷该国的阿片类药物流行，在年轻人中呈上升趋势。HCV相关肝病是肝移植的主要指征。一种有效的疫苗对于控制和预防HCV感染至关重要。虽然这种疫苗需要诱导细胞免疫和体液免疫，但本综述重点关注所需的抗体反应。对于高度可变的病毒，如HCV，介导广泛病毒中和的单克隆抗体的分离和表征是疫苗设计的重要指导。病毒包膜糖蛋白E1和E2是这些抗体的主要靶点。由于更高的抗体靶向性反映出这些表位具有更高程度的免疫原性，因此对E2蛋白上的表位研究比对E1上的表位更广泛。E2表位总体上组织成离散的重叠表位簇，范围从高度保守到高度可变。E1和E1E2上的其他表位也是中和抗体的靶点。综上所述，这些区域对疫苗设计很重要。疫苗设计的另一个要素基于有关病毒如何从广泛中和抗体中逃逸的信息。逃逸突变可发生在参与抗体结合的表位内以及不参与其表位的区域，但仍会降低中和抗体的效率。了解保护性B细胞反应的特异性、这些表位在E1、E2和E1E2上的分子位置以及使病毒能够负向调节对这些区域的中和抗体反应的机制，将为疫苗设计提供必要的指导。
