Aside from mechanisms to escape innate immunity, HCV also employs strategies to escape host adaptive immunity. Adaptive immune responses are mediated by the humoral and cellular immune systems. HCV-specific T lymphocytes are detectable 5 to 9 weeks after infection [11,12] which coincides with the onset of hepatitis. Both CD4+ and CD8+ T cells have been shown to play major roles in the outcome of HCV infection. CD8+ T cells inhibit HCV replication by cytolytic and non-cytolytic effector mechanisms [13], which are highly dependent on sufficient CD4+ T-cell cooperation. Indeed, vigorous peripheral and intrahepatic virus-specific T cell responses that target multiple epitopes have been described in patients who recover from HCV infection [5,11]. Consistent with these findings, a weak and functionally impaired T cell response was reported in patients who fail to clear the virus [13]. Viral escape, lack of CD4+ T-cell cooperation, and regulatory T cell suppression are all factors that potentially contribute to exhausting T cell responses in chronically infected patients [13].

In contrast to T cell responses, humoral responses have long been thought to play a marginal role in the outcome of HCV infection [14]. Unfortunately, studies of host neutralizing responses against HCV have historically been hampered by the lack of a convenient tissue culture system for HCV entry and infection. However, within the last decade, the development of model systems enabling study of HCV entry has significantly advanced our understanding of viral entry and escape. These models have reenergized interest in the role of neutralizing antibodies (nAbs) in the pathogenesis of liver disease and their potential in development of antivirals and vaccines.

Initial HCV attachment to the cell surface is likely facilitated by interaction with attachment factors like glycosaminoglycans [18,19] and probably low-density lipoprotein (LDL) receptor [20], though this internalization pathway might not lead to sustained viral infection [21,22]. Upon initial attachment, at least six host entry factors are important for particle internalization. These include scavenger receptor class B type 1 (SR-BI), CD81, the tight junction proteins claudin 1 (CLDN1) and occludin (OCLN) [23], the receptor tyrosine kinases [24] and the Niemann-Pick C1-like 1 cholesterol absorption receptor [25]. Functional analysis and neutralization experiments using sera from chronically HCV infected patients have demonstrated that host neutralizing responses target viral entry at a step after initial HCV binding; most likely by interrupting HCV E2-CD81 or HCV E2-SR-BI interactions, or by inhibiting membrane fusion [26]. Indeed, several E2 domains have been shown to play pivotal roles in viral entry and neutralization. Two regions in the E2 envelope glycoprotein have increased genetic variability within a quasispecies and among genotypes and have therefore been identified as hypervariable regions (HVR). The first 27 amino acids of E2 compose the first HVR (HVR1), which plays an important role in viral fitness, likely due to the involvement of SR-BI-mediated entry [27], assembly, and release of virus particles [28], as well as the HCV membrane fusion process [28]. Although HVR1 is a prime target for neutralizing antibodies, the antibodies that target HVR1 exhibit poor cross-neutralization potency across different HCV isolates due to the region’s high variability [29]. Both deletion of HVR1 and insertion of single mutations in this region significantly increase sensitivity of HCV variants for neutralization by monoclonal antibodies (mAbs) or patient-derived sera [17,30]. Antibodies that demonstrate broadly neutralizing activity tend to be directed against conserved and conformational epitopes within E2 and most often inhibit the interaction between CD81 and E2 [31,32,33,34,35,36,37,38,39,40]. The region located immediately downstream of HVR1 has been shown to contain a potent and highly conserved epitope [41]. This epitope is defined by the mouse mAb AP33 and the rat mAb 3/11. These antibodies inhibit interactions between E2 and either CD81 [34] or heparan sulfate [42]. Recently, conformational and widely conserved epitopes were identified in E1 and E2 [38,43,44,45]. The human mAb AR3, which defines one of these epitopes (aa 396–424; 436–447; 523–540), neutralizes genetically diverse HCV isolates and protects against challenge of heterologous HCV quasispecies in a human liver–chimeric mouse model [38]. Similar antibodies recognizing conformational epitopes, in this case defined by the mouse mAb D32.10 (aa 297–306; 480–494 and 613–621), were observed to circulate at high levels in the sera of patients with resolved HCV infection [44,45].

Two years later, Feray et al. studied retrospectively a cohort of patients who underwent LT due to hepatitis B virus- (HBV) (210/428) or HCV-induced (218/428) liver cirrhosis. Anti-HBV immunoglobulins, which may have incidentally been contaminated with anti-HCV immunoglobulins, were administered to 46 of 218 of the previously HCV-infected patients. Following transplantation, incidence of HCV viremia was lower in patients receiving immunotherapy (54%) than in patients whose therapy did not include anti-HCV antibodies (94%) [51]. Moreover, among the 210 patients who were HCV-negative before LT, acquired HCV infection was less frequently observed in those patients who received immunotherapy than those who did not (26% vs. 47%).

These initial observations indicate the potential contribution of neutralizing antibodies in viral control. Subsequently, the use of HCVpp bearing envelope glycoproteins of different genotypes or different patient isolates has allowed more thorough characterization of the role of neutralizing antibodies in both spontaneous control of infection and protection against re-infection.

The authors declare no conflict of interest.