Sustained E2 antibody response correlates with reduced peak viremia after hepatitis C virus infection in the chimpanzee

Abstract

A t least 170 million people worldwide are persistently infected with hepatitis C virus (HCV), which is the most common reason for liver transplantation. An estimated 2.3 to 4.7 million people become newly infected every year, but an effective vaccine is not yet available. 1,2 Six different genotypes and a variety of quasispecies of HCV pose a major challenge for the development of an effective HCV vaccine. At present the chimpanzee is the only reliable experimental animal model in which to investigate the early events after HCV infection and to evaluate the efficacy of vaccine candidates. Since HCV-specific T-cell immunity has been known to be important in the control of HCV infection, 3-5 a substantial effort has been focused on the induction of vigorous HCV-specific T-cell immunity. Although a neutralizing antibody was considered to be crucial for vaccine-mediated protection against initial virus infection by blunting the infection at an early stage, 6 there have been few reports demonstrating the role of the antibody in the prevention of HCV infection. Vaccination with recombinant E1/E2 proteins in chimpanzees, albeit transient, induced strong antibody responses that were responsible for the prevention of a low dose of ho-

Hepatitis C virus resistance to broadly neutralizing antibodies measured using replication-competent virus and pseudoparticles

“…These HCVcc have been used to further define viral entry pathways (Brimacombe et al, 2011;Carlsen et al, 2013;Mathiesen et al, 2015;Timpe et al, 2008) and to show that broadly neutralizing monoclonal antibodies (bNAbs) can prevent HCV infection in animal models (Forns et al, 2000;Morin et al, 2012;Youn et al, 2005). Panels of HCVcc expressing E1E2 from multiple genotypes have also been used to measure neutralizing breadth of bNAbs (Carlsen et al, 2014;Keck et al, 2008Keck et al, , 2013Law et al, 2008).…”

Vaccine-induced early control of hepatitis C virus infection in chimpanzees fails to impact on hepatic PD-1 and chronicity

“…2 Following a period of acute viremia and elevated serum ALT activity, approximately 70% of infected individuals develop persistent HCV infection leading to a slowly progressive chronic hepatitis with the subsequent sequelae. 3 The specific events leading to persistent HCV infection remain unclear, and it is apparent that there is a complex interaction between virus and host, in which both adaptive [4][5][6][7][8][9][10] and innate 11 responses 12 have been implicated, both influenced by the potentially tolerogenic liver environment. 3,[13][14][15] Analysis of peripheral blood samples and, where possible, of liver biopsies from both humans and chimpanzees has revealed immune correlates of viral clearance implicating an important role for nonstructural protein 3 (NS3)-specific cellular immune responses in the control and clearance of HCV infection.…”

Contribution of Redox Status to Hepatitis C Virus E2 Envelope Protein Function and Antigenicity

“…E2 was the focus of the present study because: (i) E2 is the larger of the two envelope proteins, a Ϸ370 residue polypeptide including 18 Cys in its outer membrane region; (ii) E2 mediates virus attachment to cell receptor(s) such as CD81 (10 -12), and by analogy with other viral subunits responsible for receptor binding that also exhibit a high Cys content (7), E2 is a candidate-substrate for redox reactions during entry; and (iii) E2 is the target of a neutralizing immune response, anti-E2 antibodies protecting from infection and making the protein a candidate vaccine component (13)(14)(15)(16). The E2 sequence is variable, however, which facilitates escape from the host immune response.…”