Mouse Models for Studying HCV Vaccines and Therapeutic Antibodies

Abstract

In spite of the immense progress in hepatitis C virus (HCV) research, efforts to prevent infection, such as generating a vaccine, have not yet been successful. The high price tag associated with current treatment options for chronic infection and the spike in new infections concurrent with growing opioid abuse are strong motivators for developing effective immunization and understanding neutralizing antibodies’ role in preventing infection. Humanized mice—both human liver chimeras as well as genetically humanized models—are important platforms for testing both possible vaccine candidates as well as antibody-based therapies. This chapter details the variety of ways humanized mouse technology can be employed in pursuit of learning how HCV infection can be prevented.

Animal Models Used in Hepatitis C Virus Research

“…Genetic accessibility, quick generation time, low maintenance costs, and well-established sources and protocols relative to other potential vertebrate animal models make them a preferred workhorse in many areas of research. As discussed previously, because of the inability of HCV to infect mice [113][114][115], many alternative approaches have been taken to use mice productively in HCV research. In addition to the study of rodent hepatotropic viruses, which serve as surrogates for HCV infection (discussed in Section 3.3), mice have been used to study HCV infection by transgenic expression of the partial or entire HCV genome along with specific human factors known to interact with the virus and/or xenotransplantation of human hepatocytes and immune cells.…”

“…These have been used to great advantage in HCV research. Mice which can be successfully engrafted with both human liver tissue and immune system cells have been the subject of numerous reviews [26,115,[132][133][134]. The earliest use of chimeric engrafted mice in HCV research used severe combined immunodeficient (SCID) mouse bone marrow cells engrafted into irradiated beige/nude/x-linked immunodeficient mice (BNX mice) [72].…”

Mouse Models as Resources for Studying Infectious Diseases

“…56 Although genetically humanized mouse strains can be powerful tools for modeling infection with some viral pathogens, for other viruses, such as HCV, several genes regulate host range, making it difficult to fully recapitulate the human factors that promote pathogen replication or disease in either standard or genetically humanized mice. 57,58 Furthermore, differences between the mouse and human immune system may limit the utility of standard or modified mouse strains as models for studying host immune responses or disease pathogenesis. 59 To overcome these problems, the research community has used mice engrafted with human tissues to model human responses to infection.…”

Antibody Responses in Hepatitis C Infection

“…Recent advances in the HCV culture system (Lindenbach et al 2005;Wakita et al 2005;Zhong et al 2005;Lu et al 2014;Kato et al 2019) and virus engineering (Pietschmann 2009;Li et al 2012;McClure et al 2016), virus neutralization assays (Bartosch et al 2003;Hsu et al 2003;Bailey et al 2019b;Prentoe and Bukh 2019;Urbanowicz et al 2019), and small animal models (Gaska et al 2019) have enabled the field to monitor nAb responses in infected or vaccinated subjects, to identify antibodies recognizing conserved neutralizing epitopes shared by diverse HCV strains, and to demonstrate conclusively in passive transfer experiments that potent nAbs can protect against HCV quasispecies (see below).…”