The recent discovery of natural immunity to the hepatitis C virus and vaccine efficacy in the chimpanzee challenge model has allowed optimism about the development of at least a partly effective vaccine against this heterogeneous pathogen that is responsible for much of the chronic liver disease around the world. The immune systems of some infected individuals can spontaneously clear the virus, whereas other people need treatment with antivirals that work partly by stimulating humoral and cellular immune responses. Therefore, therapeutic vaccine strategies are also being pursued to improve treatment outcome.
"The HCV genome polyprotein is cleaved into 11 viral proteins, out of which five are structural (core protein p21, core protein p19, envelope glycoprotein E1, envelope glycoprotein E2 and core protein p7) and six are non-structural (protease NS2–3, serine protease NS3, non-structural protein 4A, non-structural protein 4B, non-structural protein 5A, and RNA-directed RNA polymerase) (Lidenbach, Thiel, & Rice, 2007; Krekulova, Rehak, & Riley, 2006). The envelope glycoprotein (E protein in flavivirus and E1 and E2 protein in Hepacivirus) is the principal protein of the virion in all of flaviviridae family, which mediates the virus attachment and membrane fusion, thereby playing an important role during infection of host cells, and is considered to be a potential vaccine and therapeutic target in the flaviviridae family (Geiss, Stahla, Hannah, Gari, & Keenan, 2009; Helle & Dubuisson, 2008; Houghton & Abrignani, 2005; Kachko et al., 2011; Law et al., 2013; Stamataki, Coates, Abrignani, Houghton, & McKeating, 2011; Voisset & Dubuisson, 2004). "
[Show abstract][Hide abstract] ABSTRACT: Abstract Hepatitis C Virus (HCV) is the leading cause of chronic liver disease in humans. The envelope proteins of HCV are potential candidates for vaccine development. The absence of three-dimensional (3D) structures for the functional domain of HCV envelope proteins E1.E2 monomer complex has hindered overall understanding of the virus infection, and also structure-based drug design initiatives. In this study, we report a 3D model containing both E1 and E2 proteins of HCV using the recently published structure of the core domain of HCV E2 and the functional part of E1 and investigate immunogenic implications of the model. HCV [E1.E2] molecule is modeled by using aa205-319 of E1 to aa421-716 of E2. Published experimental data was used to further refine the [E1.E2] model. Based on the model we predict 77 exposed residues and several antigenic sites within the [E1.E2] that could serve as vaccine epitopes. This study identifies 8 peptides which have antigenic propensity and have two or more sequentially exposed amino acids and 12 singular sites are under negative selection pressure that can serve as vaccine or therapeutic targets. Of special interest is 285FLVGQLFTFSPRRHW299 which has 5 negatively selected sites (L286, V287, G288, T292, G303) with three of them sequential and 4 amino acids exposed (F285, L286, T292, R296). This peptide in the E1 protein maps to Dengue envelope vaccine target identified previously by our group. Our model provides for the first time an overall view of both the HCV envelope proteins thereby allowing researchers explore structure-based drug design approaches.
"In preclinical studies conducted in chimpanzees, the vaccine induced high titres of E1 and E2 specific antibodies and prevented five chimpanzees from becoming infected with a homologous challenge of virus and protection correlated with the presence of high titre anti-E2 antibodies (Choo et al., 1994). Challenge of the chimpanzees with a closely related heterologous virus strain resulted in infection in all cases; all but one vaccinee did not progress to chronic infection, suggesting the vaccine does induce a degree of protective but not sterilizing immunity (Houghton and Abrignani, 2005). "
[Show abstract][Hide abstract] ABSTRACT: Despite 20 years of research, a vaccine to prevent hepatitis C virus (HCV) infection has not been developed. A vaccine to prevent HCV will need to induce broadly reactive immunity able to prevent infection by the 7 genetically and antigenically distinct genotypes circulating world-wide. HCV encodes two surface exposed glycoproteins, E1 and E2 that function as a heterodimer to mediate viral entry. Neutralizing antibodies (NAbs) to both E1 and E2 have been described with the major NAb target being E2. The function of E2 is to attach virions to host cells via cell surface receptors that include, but is not limited to, the tetraspanin CD81 and scavenger receptor class B type 1. However, E2 has developed a number of immune evasion strategies to limit the effectiveness of the NAb response and possibly limit the ability of the immune system to generate potent NAbs in natural infection. Hypervariable regions that shield the underlying core domain, subdominant neutralization epitopes and glycan shielding combine to make E2 a difficult target for the immune system. This review summarizes recent information on the role of NAbs to prevent HCV infection, the targets of the NAb response and structural information on glycoprotein E2 in complex with neutralizing antibodies. This new information should provide a framework for the rational design of new vaccine candidates that elicit highly potent broadly reactive NAbs to prevent HCV infection.
Frontiers in Microbiology 07/2014; 5:329. DOI:10.3389/fmicb.2014.00329 · 3.99 Impact Factor
"Non-sterilizing protective immunity exists, supporting the idea that viral persistence may be prevented by vaccination . However , heterogeneity and genetic variability of HCV is a major obstacle for developing a HCV vaccine . Early, strong, and multispecific T-cell responses, targeting a large number of epitopes of HCV proteins are associated with clearing viremia and avoiding viral escape  . "
[Show abstract][Hide abstract] ABSTRACT: HCV is a worldwide health problem despite the recent advances in the development of more effective therapies. No preventive vaccine is available against this pathogen. However, non-sterilizing immunity has been demonstrated and supports the potential success of HCV vaccines. Induction of cross-neutralizing antibodies and T cell responses targeting several conserved epitopes, have been related to hepatitis C virus (HCV) clearance. Therefore, in this work, the immunogenicity of a preparation (MixprotHC) based on protein variants of HCV Core, E1, E2 and NS3 was evaluated in mice and monkeys. IgG from MixprotHC immunized mice and monkeys neutralized the infectivity of heterologous HCVcc. Moreover, strong CD4+ and CD8+ T cells proliferative and IFN-γ secretion responses were elicited against HCV proteins. Remarkably, immunization with MixprotHC induced control of viremia in a surrogate challenge model in mice. These results suggest that MixprotHC might constitute an effective immunogen against HCV in humans with potential for reducing the likelihood of immune escape and viral persistence.
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