Hepatitis C Virus Vaccines in the Era of New Direct-acting Antivirals

Chao Shi; Alexander Ploss

Disclosures

Expert Rev Gastroenterol Hepatol. 2013;7(2):171-185. 

In This Article

Adapting HCV to Infect Nonpermissive Species

The full life cycle of HCV can be divided into three critical steps: cell entry, replication and assembly/egress/release of viral particles. Host factors are involved in each step. For entering its target cell, the hepatocyte, HCV requires numerous cellular factors, including glycosaminoglycans,[126,127] low-density lipoprotein receptor, scavenger receptor class B type I (SCARB1),[128–131] CD81,[132] two tight junction proteins, claudin-1[133] and occludin (OCLN).[134,135] More recently, the cholesterol absorption receptor Niemann-Pick C1-like 1[136] and two receptor tyrosine kinases, EGF receptor and EphrinA2[137] have been implicated in the viral uptake pathway into human cells (reviewed in [138]). The difference in the ability of HCV to engage these host factors helps define the species tropism of HCV. In murine cells, HCV appears to less efficiently engage CD81 and OCLN, which precludes viral entry.[134] However, given the error-prone replication of HCV genome, it is conceivable to 'train' HCV to utilize murine orthologs of HCV entry factors. Critical proof-of-concept for this approach was recently provided in a study, in which a strain of HCV was selected to use murine CD81.[139] This virus acquired mutations in the E1 and E2 envelope proteins, which facilitated viral entry into murine cells in the absence of human entry factors. It remains to be tested whether the 'murine-tropic' HCV can actually infect mice in vivo. A mouse model would certainly be very attractive for HCV vaccine research; as multiple inbred and outbred lines are available, mice can be generated in large numbers at fairly low costs and numerous tools to analyze vaccine and virally induced immune responses are available. However, since the evolutionary divergence of mouse and man 65 million years ago, these two species have inhabited different ecological niches and have been challenged with minimally overlapping groups of pathogens. Therefore, the human and mouse immune systems, evolving to meet these challenges, have accumulated many differences,[140] making genes related to immunity, together with genes involved in reproduction and olfaction, the most divergent between the two species.[141] These differences are likely to affect the quality of an antiviral immune response and consequently may lessen the utility of the system for testing vaccines and therapeutics targeting human HCV.

Consequently, adaptation of HCV to other, more closely related species to humans needs to be pursued to ameliorate some of the caveats. Small nonhuman primates, such as Rhesus monkeys are more similar to humans but they are also resistant to HCV infection[142] possibly due to the inability of HCV to counteract antiviral innate immune responses.[143] Nonetheless, adaptation of HCV to small nonhuman primates offers several considerable advantages. Given the greater similarity to humans, it may potentially be easier to overcome putative incompatibilities between virally encoded proteins and host factors. Furthermore, rhesus monkeys have been extensively used in biomedical research, and a plethora of tools is available. Studies conducted in monkeys may translate more readily into clinical results. Macaques also offer a better platform for pharmacokinetic studies for HCV vaccines and drugs. In addition, the fact that a large fraction of HCV carriers is coinfected with HIV must be considered when assessing vaccine candidates. A macaque model for HIV/HCV coinfection is of interest and significant clinical relevance, especially when a simian-tropic HIV-1 is already available.[144,145]

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