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

Susan L. Uprichard, PhD

Director of Hepatology ResearchDirector of Hepatology ResearchLoyola University Medical CenterLoyola University Medical Center

Department of MedicineDepartment of MedicineSection of HepatologySection of Hepatology

HepNet 2013

HCV Virology

Approximately 170 million people worldwideApproximately 170 million people worldwideare infected with HCVare infected with HCV

World Health Organization. Hepatitis C - Global Surveillance Update

<1%<1%

1 - 2.4%1 - 2.4%

2.5 - 4.9%2.5 - 4.9%

5 - 10%5 - 10%

>10%>10%n/an/a

Acute infection – typically asymptomatic

The majority of those who becomeinfected remain chronically infected

persistent hepatitissteatosisliver cirrhosishepatocellular carcinoma

HCV InfectionHCV Infection

TrichromeTrichromeStainedStainedFibrosisFibrosis

Picture from:Picture from: Dr. GuzmanDr. Guzman

No preventative vaccineNo preventative vaccine

Only a fraction of patients respond to Only a fraction of patients respond to available IFN-based therapiesavailable IFN-based therapies

limited efficacylimited efficacyexpensiveexpensiveadherenceadherenceadverse side effectsadverse side effects

Many do not know they are infectedMany do not know they are infectedUnknown who will develop progressive diseaseUnknown who will develop progressive diseaseUnknown who will respond to therapyUnknown who will respond to therapy


No preventative vaccineNo preventative vaccine

Only a fraction of patients respond to Only a fraction of patients respond to available IFN-based therapiesavailable IFN-based therapies

limited efficacylimited efficacyexpensiveexpensiveadverse side effectsadverse side effects

Many do not know they are infectedMany do not know they are infectedUnknown who will develop progressive diseaseUnknown who will develop progressive diseaseUnknown who will respond to therapyUnknown who will respond to therapy


Better understanding of HCV and the host factors that determine outcome and treatment response

is needed to improve treatment options

19719755 Description of non-A, non-B Description of non-A, non-B

hepatitishepatitis

19891989Identification of HCVIdentification of HCV

HCV Timeline

Ability to screen bloodAbility to screen blood

15 years

FamilyFamily:: Flaviviridae (enveloped, positive-strand RNA viruses) Flaviviridae (enveloped, positive-strand RNA viruses)

HCV GenomeHCV Genome:: contains a single ORF that encodes a polyprotein (~3011aa) contains a single ORF that encodes a polyprotein (~3011aa) Translated in the cytoplasm by the host cellTranslated in the cytoplasm by the host cell Polyprotein processed by host & viral proteasesPolyprotein processed by host & viral proteases

Identification of possible HCV antiviral targets Identification of possible HCV antiviral targets (protease/polymerase)(protease/polymerase)

RNA= 9.6kbRNA= 9.6kb

HCV VirologyHCV Virology


hepatitishepatitis


19981998 IFN / ribavirin combination therapyIFN / ribavirin combination therapy

19991999Replicon Replicon system system Replicon Replicon system system

HCV Timeline


19971997 Infectious clone in chimpanzeesInfectious clone in chimpanzees

10 years

Recombinant HCV RNA containing a selection markerRecombinant HCV RNA containing a selection marker

How replicons work:How replicons work: Introduce RNA into cellIntroduce RNA into cellViral replication proteins are madeViral replication proteins are madeViral proteins replicate the RNA.Viral proteins replicate the RNA.

HCV RepliconsHCV Replicons

Using the selection marker couldUsing the selection marker couldselect for cells that replicate the repliconselect for cells that replicate the replicon

HCV RepliconsHCV Replicons

Allowed for robust antiviral drug screening (protease / polymerase inhibitors)


hepatitishepatitis



20052005Infectious HCV cell culture system

Infectious HCV cell culture system


HCV Timeline


20122012Protease inhibitorsProtease inhibitors

Polymerase inhibitorsPolymerase inhibitors


H24

76L

d11 d14 d22

d11 d14 d22

JFH

-1

HCV Infection System


hepatitishepatitis



20052005Infectious HCV cell culture system

Infectious HCV cell culture system

20132013


HCV Timeline

HCV Mouse ModelHCV Mouse Model


20122012Protease inhibitorsProtease inhibitors

Polymerase inhibitorsPolymerase inhibitors

Entry inhibitorsEntry inhibitorsHost factor inhibitorsHost factor inhibitors


HCV Life Cycle

From Ralf Bartenschlager

HOST FACTORS INVOLVED IN HCV ENTRY

Niemann-Pick C1 Like 1 ProteinNiemann-Pick C1 Like 1 Protein( NPC1L1 )( NPC1L1 )

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

145 kDaLEL1 LEL2

LEL3

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?

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

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