The Chimpanzee Model of Viral Hepatitis: Advances in Understanding the Immune Response and Treatment of Viral Hepatitis

Abstract

Chimpanzees (Pan troglodytes) have contributed to diverse fields of biomedical research due to their close genetic relationship to humans and in many instances due to the lack of any other animal model. This review focuses on the contributions of the chimpanzee model to research on hepatitis viruses where chimpanzees represented the only animal model (hepatitis B and C) or the most appropriate animal model (hepatitis A). Research with chimpanzees led to the development of vaccines for HAV and HBV that are used worldwide to protect hundreds of millions from these diseases and, where fully implemented, have provided immunity for entire generations. More recently, chimpanzee research was instrumental in the development of curative therapies for hepatitis C virus infections. Over a span of 40 years, this research would identify the causative agent of NonA,NonB hepatitis, validate the molecular tools for drug discovery, and provide safety and efficacy data on the therapies that now provide a rapid and complete cure of HCV chronic infections. Several cocktails of antivirals are FDA approved that eliminate the virus following 12 weeks of once-per-day oral therapy. This represents the first cure of a chronic viral disease and, once broadly implemented, will dramatically reduce the occurrence of cirrhosis and liver cancer. The recent contributions of chimpanzees to our current understanding of T cell immunity for HCV, development of novel therapeutics for HBV, and the biology of HAV are reviewed. Finally, a perspective is provided on the events leading to the cessation of the use of chimpanzees in research and the future of the chimpanzees previously used to bring about these amazing breakthroughs in human healthcare.

Hypervariable Region 1 in Envelope Protein 2 of Hepatitis C Virus: A Linchpin in Neutralizing Antibody Evasion and Viral Entry

“…Chimpanzees represent the first infection model of HCV and it has been used extensively to study HCV pathogenesis ( 123 – 125 ), including the role of HVR1. Incubation of hyper-immune serum raised against HVR1 peptide with a well-characterized homologous HCV chimpanzee inoculum prevented acute HCV infection in chimpanzees in one out of two cases ( 126 ), thus identifying HVR1 as the first HCV neutralization epitope.…”

Utility of Common Marmoset (Callithrix jacchus) Embryonic Stem Cells in Liver Disease Modeling, Tissue Engineering and Drug Metabolism

“…The cloning of HCV genome from a chimpanzee that was infected with non-A, non-B hepatitis [ 61 ] has shed light on NHPs as useful animal models for viral hepatitis, which eventually resulted in the development of vaccines against HAV and HBV infections. In fact, chimpanzees are most suitable hosts for hepatitis viruses A–D studies [ 62 , 63 , 64 ]. But their use in experimental research is severely restricted as they are endangered species, controversial with animal rights advocates, and due to the high costs involved [ 63 ].…”

Nonhuman Primates and Translational Research: Progress, Opportunities, and Challenges

“…Examples include studies of several visual abnormalities (Mustari 2017), development of HIV/AIDS vaccines and therapeutics (Van Rompay 2017; Veazey and Lackner 2017), and therapies for tuberculosis (Foreman et al 2017). An extreme example of this exclusivity is the essential use of chimpanzees (Pan troglodytes), relative even to macaques or other monkeys, for the development of vaccines against infection by Hepatitis A and B viruses and of therapeutics to cure Hepatitis C disease (Lanford et al 2017).…”

“…Significantly, animal rights activity appears to be aimed at influencing members of the US Congress or the executive branch, who have direct influence over the budgets that are provided by the US government to the funding agencies. Recent examples include the influence of the animal rights organizations on the NIH decision to prohibit research using chimpanzees (Reardon 2015, see also commentary in this issue by Veazey andLanford et al 2017) and the mandate by a small number of US Congress members in 2016 for the NIH to review its policies on the oversight of NHP research (Grimm 2016; see the NIH final report at https://www.cnprc. ucdavis.edu/wp-content/uploads/2017/01/NIH-NHP-Workshop-Report.pdf, which reaffirmed the importance of NHP research).…”