Transcript HCV Virology Simplified. S Uprichard, PhD

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?