New Insights in Recurrent HCV Infection after Liver Transplantation

Hsu, Shih-Hsien; Yeh, Ming-Lun; Wang, Shen-Nien

Cells through E2. Humoral responses are often thought to play a key role in controlling HCV infection [81] . In clinical setting, patients spontaneously resolving from acute HCV infection tend to have an early induction of neutralizing antibody response. In contrast, chronic infection patients have a delayed initiation of neutralizing antibody response. Moreover, the variety of strategies the virus evolves to escape antibodies-mediated neutralization, including the accelerated evolution and the diversity of HCV [82] . Overall, the capacity of HCV to mutate continuously allows a high plasticity and an ability of the virus to adapt to variable environmental conditions and escape the host's immune responses leading to HCV persistene. HCV entry to the hepatocytes requires interaction of its viral envelope glycoproteins (E1 and E2) and the cell membrane [83] . Both E1 and E2 contain putative fusion domains [84] . While little is known about the role of E1 in HCV entry, several domains in E2 have been defined to bind to CD 81 and scavenger receptor class B type I (SR-BI), two important host factors (described in the next paragraph). These interactions through E2 glycoprotein help HCV evade host immune responses and enter the hepatocytes. For example, hypervariate region 1 (HVR1), the first 27 amino acids of E2, plays an important role in viral fitness. It has been demonstrated that HVR1 was involved in SR-BI-mediated HCV entry [85] . Therefore, HVR1 has been suggested to be a target for neutralizing antibodies, but its high variability results in poor crossneutralization potency of antibodies across different HCV isolates [86] . It is well known that host humoral responses are thought to play a critical role in controlling HCV infection. Several studies reported that broadly neutralizing antibodies might be directed against conserved conformational epitopes within E2 and mostly inhibit E2-CD81 interaction [87, 88] . Currently, new conformational and conserved epitopes have been identified in the N-terminal part of E2 [89] . The conserved nature of these epitopes holds great promise for the development of potent inhibitors for HCV entry.