The 2016 Lasker-DeBakey Clinical Medical Research Award: Innovative hepatitis C virus (HCV) replicons leading to drug development for hepatitis C cure

Milestones in the discovery of hepatitis C

“…In addition there were many cases of “nosocomial” hepatitis[ 21 ] and cryptogenic hepatitis and a lack of diagnostic tests. The journey to unravel this problem took another 39 years, 14 years from the identification of non-A non-B hepatitis to the discovery of the HCV and 25 years from the discovery of HCV in 1989 to the approval of one of the most prescribed direct acting antiviral agents (DAA) Sofosbuvir in 2013 for the treatment of hepatitis C[ 22 ]. In all, those 39 years don’t seem too bad now when we look at the progress made from those early clinical and epidemiologic studies by Alter and others up to the incredibly creative and imaginative pharmacological approach to therapy involving the design of DAA that inhibit HCV infection by blocking viral assembly and replication at the present time[ 22 ].…”

“…At this point there was another crucial question, that is whether this virus could reproduce infection if inoculated into an experimental model, hence probing that the now called HCV was the causative agent of the formerly known NANBH. Rice C a researcher at the University of Washington who had been working with molecular virology of Flavivirus [ 22 ] focused on dissecting HCV gene expression using blood from infected chimpanzees to introduce DNA fragments into bacteria to express individual protein fragments. Those products were then screened with the antiviral antibodies until they could isolate one positive clone.…”

“…When he injected this genome into the liver of chimpanzees clinical signs of hepatitis ensued and there was virus present in the blood producing now the evidence that the clone of the HCV could produce the disease associated with hepatitis infection[ 22 , 30 ]. That was a very important advance because the development of HCV replicons provided a live HCV system in the laboratory where viral replication, pathogenesis and evolution in culture could be studied in a viable in vitro replication system[ 22 ]. Later on newer constructs were obtained with higher replicative ability in vitro [ 22 ].…”

“…That was a very important advance because the development of HCV replicons provided a live HCV system in the laboratory where viral replication, pathogenesis and evolution in culture could be studied in a viable in vitro replication system[ 22 ]. Later on newer constructs were obtained with higher replicative ability in vitro [ 22 ]. This was another milestone.…”

“…Within 1 year of the cloning of HCV the nucleotide sequence of the entire viral genome was determined and the agent was characterized as a single-stranded positive-sense RNA virus of about 9600 nucleotides in length[ 2 , 31 ]. The advent of functional replicons also enabled the assay development for antiviral drug development which made the search for effective anti-viral drugs much easier[ 22 ]. Another collaborator of Rice, Ralf Bartenschlager, a molecular biologist who had previously worked with HBV, successfully replicated HCV genomic RNA in a human hepatoma cell line Huh7[ 32 ].…”