Susan L. Uprichard, PhD Director of Hepatology Research Loyola University Medical Center

1. HCV Virology Susan L. Uprichard, PhD Director of Hepatology Research Loyola University Medical Center Department of Medicine Section of Hepatology HepNet 2013

2. Approximately 170 million people worldwide are infected with HCV <1% 1 - 2.4% 2.5 - 4.9% 5 - 10% >10% World Health Organization. Hepatitis C - Global Surveillance Update n/a

3. 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

4. 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

5. Better understanding of HCV and the host factors that determine outcome and treatment response is needed to improve treatment options HCV Infection • No preventative vaccine • Only a fraction of patients respond to • available IFN-based therapies • limited efficacy • expensive • adverse side effects • Many do not know they are infected • Unknown who will develop progressive disease • Unknown who will respond to therapy

6. HCV Timeline Identification of HCV 1989 Ability to screen blood 15 years 1975 Description of non-A, non-B hepatitis

7. 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)

8. HCV Timeline 1998 10 years IFN / ribavirin combination therapy Replicon system 1999 1997 Infectious clone in chimpanzees Identification of HCV 1989 Ability to screen blood 1975 Description of non-A, non-B hepatitis

9. 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.

10. HCV Replicons Using the selection marker could select for cells that replicate the replicon Allowed for robust antiviral drug screening (protease / polymerase inhibitors)

11. HCV Timeline Polymerase inhibitors 1998 Infectious HCV cell culture system 2005 2012 IFN / ribavirin combination therapy Protease inhibitors Replicon system 1999 1997 Infectious clone in chimpanzees Identification of HCV 1989 Ability to screen blood 1975 Description of non-A, non-B hepatitis

12. HCV Infection System

13. HCV Timeline Entry inhibitors Host factor inhibitors HCV Mouse Model 2013 Polymerase inhibitors 1998 Infectious HCV cell culture system 2005 2012 IFN / ribavirin combination therapy Protease inhibitors Replicon system 1999 1997 Infectious clone in chimpanzees Identification of HCV 1989 Ability to screen blood 1975 Description of non-A, non-B hepatitis

14. HCV Life Cycle

15. From Ralf Bartenschlager

16. HOST FACTORS INVOLVED IN HCV ENTRY

17. SSD Niemann-Pick C1 Like 1 Protein ( NPC1L1 ) LEL2 LEL1 145 kDa LEL3 • 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

18. HOST FACTORS SERVE AS POTENTIAL ANTIVIRAL TARGETS

19. HCV seroprevalence across ezetimibe use P-value: 0.02 (Adjusted sampling & design corrections applied for analyses)

20. WHAT DO HOST FACTORS HAVE TO TEACH US ABOUT HCV?