Abstract
The ability to use structure-based design and engineering to control the molecular shape and reactivity of an immunogen to induce protective responses shows great promise, along with corresponding advancements in vaccine testing and evaluation systems. We describe in this review new paradigms for the development of a B cell-based HCV vaccine. Advances in test systems to measure in vitro and in vivo antibody-mediated virus neutralization include retroviral pseudotype particles expressing HCV E1E2 glycoproteins (HCVpp), infectious cell culture-derived HCV virions (HCVcc), and surrogate animal models mimicking acute HCV infection. Their applications have established the role of broadly neutralizing antibodies to control HCV infection. However, the virus has immunogenic regions in the viral envelope glycoproteins that are associated with viral escape or non-neutralizing antibodies. These regions serve as immunologic decoys that divert the antibody response from less prominent conserved regions mediating virus neutralization. This review outlines the immunogenic regions on E2, which are roughly segregated into the hypervariable region 1 (HVR1), and five clusters of overlapping epitopes designated as antigenic domains A-E. Understanding the molecular architecture of conserved neutralizing epitopes within these antigenic domains, and how other antigenic regions or decoys deflect the immune response from these conserved regions will provide a roadmap for the rational design of an HCV vaccine.
Highlights
Chronic hepatitis C virus (HCV) infection often leads to chronic hepatitis, liver failure and hepatocellular carcinoma (Mohd Hanafiah et al, 2013)
AR5 overlaps with an antigenic domain C human monoclonal antibodies (HMAbs), FIGURE 2 | Amino acid sequence variability of HCV envelope glycoproteins E1 and E2 Sequence logos (Crooks et al, 2004) were generated using a multiple sequence alignment of approximately 400 complete E1 and E2 glycoproteins form a heterodimer (E1E2) amino acid sequences downloaded from the Los Alamos HCV database (Kuiken et al, 2005)
Over the past 5 years, a number of studies have helped to elucidate structural features of E1 and E2, as noted in recent reviews (Khan et al, 2015; Kong et al, 2015a; Pierce et al, 2016a). These have collectively shown that key epitopes targeted by broadly neutralizing antibodies on the “front layer” of E2, which corresponds to the CD81 binding face, exhibit structural heterogeneity, in particular E2 antigenic domain E (Kong et al, 2012; Li et al, 2015; Meola et al, 2015), as well as antigenic domains B and D (Kong et al, 2013; Deng et al, 2014; Keck et al, 2016b; Vasiliauskaite et al, 2017)
Summary
Chronic hepatitis C virus (HCV) infection often leads to chronic hepatitis, liver failure and hepatocellular carcinoma (Mohd Hanafiah et al, 2013). In. Vaccine Development for Hepatitis C Virus addition, reinfection remains a problem even after successful treatment in subjects with continued at risk behavior such as injection drug use. Vaccine Development for Hepatitis C Virus addition, reinfection remains a problem even after successful treatment in subjects with continued at risk behavior such as injection drug use For these reasons, an effective prophylactic vaccine is needed. The genetic diversity of HCV of at least seven HCV genotypes that differ up to 30% in nucleotide sequence, which can be further subdivided into 67 subtypes (Tarr et al, 2015), poses a major challenge to develop a pan-genotypic vaccine (Walker, 2017) Another hurdle is that immune correlates of protection have yet to be defined for HCV. Development of an effective vaccine for HCV must consider these factors
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