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

Engineering the Hosts to Accommodate HCV

Another direction researchers have taken to create an animal model is to engineer the host environment to support HCV infection. Host adaptation can be achieved by actually transplanting human tissues to humanize relevant tissue compartments or by genetic adaptation of the host species. It has been demonstrated that engraftment of human hepatocytes into suitable xenorecipients can render mice susceptible to HCV infection.[146] In these xenotransplantation models, liver injury is induced in the recipients before transplantation to provide a growth stimulus to the engrafted human hepatocytes. Currently, the urokinase plasminogen activator transgenic mouse and fumary lacetoacetate hydrolase deficient mouse, both being susceptible to endogenous liver injury, were used in combination with severe immunodeficiency for liver xenotransplantation models.[147–149] Human liver-chimeric mice can be successfully infected with HCV.[146,147,150] However, a major drawback of these human liver-chimeric mice is the lack of a functional immune system. Although the efficacy of neutralizing antibodies and antiviral drugs can be assessed in those mice, it is difficult to study the immune responses induced by vaccines. Recently, an alternative xenorecipient strain has been constructed, in which FK506 binding protein fused to active caspase 8 is transgenically expressed.[125] Upon injection of the FK506 dimerizer, AP20187 apoptosis is induced in mouse hepatocytes. Remarkably, mice injected with a mixture of autologous human hepatoblasts, nonparenchymal cells and hematopoietic stem cells resulted in measurable human hepatic and hematopoietic chimerism. Dually engrafted mice not only supported HCV viremia at very low levels but also mounted antigen-specific viral immune response.[125] Although the functionality of the human immune system still requires substantial improvement, these and similar xenotransplant models may become a suitable platform to analyze vaccine induced, human anti-HCV immunity in a small animal model.

Alternatively, mice have been genetically modified to be more permissive for HCV infection. Based on the previous discovery that human CD81 and OCLN constitute the minimal set of entry factors required for viral uptake into rodent cells,[134] mice were engineered to express adenovirally delivered human entry factors.[151] These genetically humanized mice support HCV entry. Importantly, this mouse is fully immunocompetent, and it is thus suitable for immunization and challenge studies. However, in order for this model to gain additional utility, for example, to study virus-induced immunity or to evaluate therapeutic vaccine candidates, the recapitulation of the entire life cycle in an inbred, genetically humanized mouse would be critical. Nevertheless, the introduction of a small animal model with a competent immune system, would be an enabling tool in HCV vaccine research.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....