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HCV Virology HepNet 2013 Susan L. Uprichard, PhD Director of Hepatology Research Loyola University Medical Center Department of Medicine Section of Hepatology Approximately 170 million people worldwide are infected with HCV World Health Organization. Hepatitis C - Global Surveillance Update <1% 1 - 2.4% 2.5 - 4.9% 5 - 10% >10% n/a HCV Infection Acute infection – typically asymptomatic The majority of those who become infected remain chronically infected persistent hepatitis steatosis liver cirrhosis hepatocellular carcinoma Trichrome Stained Fibrosis Picture from: Dr. Guzman HCV Infection No preventative vaccine Only a fraction of patients respond to available IFN-based therapies limited efficacy expensive adherence adverse side effects Many do not know they are infected Unknown who will develop progressive disease Unknown who will respond to therapy HCV Infection No preventative vaccine Only a fraction of patients respond to Better understanding of HCV available IFN-based therapies and the host factors that determine limited and efficacy outcome treatment response is needed to improve treatment options expensive adverse side effects Many do not know they are infected Unknown who will develop progressive disease Unknown who will respond to therapy HCV Timeline Identification of HCV 1989 15 years 1975 Ability to screen blood Description of non-A, non-B hepatitis HCV Virology RNA= 9.6kb Family: Flaviviridae (enveloped, positive-strand RNA viruses) HCV Genome: contains a single ORF that encodes a polyprotein (~3011aa) Translated in the cytoplasm by the host cell Polyprotein processed by host & viral proteases Identification of possible HCV antiviral targets (protease/polymerase) HCV Timeline 10 years Replicon system 1999 1997 Infectious clone in chimpanzees 1998 IFN / ribavirin combination therapy Identification of HCV 1989 Ability to screen blood 1975 Description of non-A, non-B hepatitis HCV Replicons Recombinant HCV RNA containing a selection marker How replicons work: Introduce RNA into cell Viral replication proteins are made Viral proteins replicate the RNA. HCV Replicons Using the selection marker could select for cells that replicate the replicon Allowed for robust antiviral drug screening (protease / polymerase inhibitors) HCV Timeline Polymerase inhibitors Infectious HCV cell culture system 2005 2012 Protease inhibitors Replicon system 1999 1997 Infectious clone in chimpanzees 1998 IFN / ribavirin combination therapy Identification of HCV 1989 Ability to screen blood 1975 Description of non-A, non-B hepatitis HCV Infection System d11 d14 d22 HCV Timeline Entry inhibitors Host factor inhibitors Polymerase inhibitors HCV Mouse Model 2013 Infectious HCV cell culture system 2005 2012 Protease inhibitors Replicon system 1999 1997 Infectious clone in chimpanzees 1998 IFN / ribavirin combination therapy Identification of HCV 1989 Ability to screen blood 1975 Description of non-A, non-B hepatitis HCV Life Cycle From Ralf Bartenschlager HOST FACTORS INVOLVED IN HCV ENTRY Niemann-Pick C1 Like 1 Protein ( NPC1L1 ) LEL1 LEL2 145 kDa LEL3 SSD • • 13 trans-membrane cell surface cholesterol transporter Altmann, et al. (2004) - Cellular cholesterol absorption and homeostasis – • NPC1L1 takes up free cholesterol into cells via vesicular endocytosis (clathrin) In most species, expression restricted to the enterocytes However - humans & chimpanzees, it is also abundant on hepatocytes HOST FACTORS SERVE AS POTENTIAL ANTIVIRAL TARGETS HCV seroprevalence across ezetimibe use HCV Positive (N=276) HCV Negative (N=15337) On ezetimibe 0.2% 99.8% Not on ezetimibe 1.7% 98.3% P-value: 0.02 (Adjusted sampling & design corrections applied for analyses) WHAT DO HOST FACTORS HAVE TO TEACH US ABOUT HCV?