hepatitis c virus casey mcgrath bio 360. epidemiology introduction to hepatitis c virus immune...
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Hepatitis C Virus
Casey McGrath
BIO 360
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• Epidemiology
• Introduction to Hepatitis C Virus
• Immune response
• Novel drug therapies
• Conclusions
Outline
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Epidemiology
Hepatitis C Virus (HCV):
• ~170 million people worldwide
• Chronic hepatitis, liver cirrhosis, hepatocellular carcinoma (HCC)
• Transmitted via blood--transfusions, intravenous drug use
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Prevalence of HCV by world region
HEPATITIS C ESTIMATED WORLD INFECTION PREVALENCE
(BY WHO REGION)
WHO Region
Total Population (Millions)
Hepatitis C Prevalence
(Rate %)
Infected Population (Millions)
Number of Countries (by WHO Region)
Where Data Unavailable
Africa 602 5.3 31.9 12
Americas 785 1.7 13.1 7
Eastern Mediterranean
466 4.6 21.3 7
Europe 858 1.03 8.9 19
South-East Asia
1500 2.15 32.3 3
Western Pacific
1600 3.9 62.2 11
Total 5811 3.1 169.7 59
Data Source: Weekly Epidemiological Record No. 49 / Dec, 1999 / WHO
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Transmission sources
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Disease statistics
Infected Individuals
Persistent Infection
Liver Disease
Death
85%
30%
1-5%
Most patients are asymptomatic and unaware they’re infected
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HCV research
• Unknowns
• No cell culture system
• No small animal model
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• Epidemiology
• Introduction to Hepatitis C Virus
• Immune response
• Novel drug therapies
• Conclusions
Outline
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HCV
• Genus Hepacivirus
• Family Flaviviridae, with classical flaviviruses and animal pestiviruses
• 6 genotypes worldwide, many subtypes and isolates based on nucleotide diversity
• Quasispecies within individual
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Distribution of Hepatitis C genotypes
From Forns and Bukh, 1999.
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HCV virion structure
Hypothesized structure:
• Icosahedral lipid membrane with E1/E2 glycoproteins
• Icosahedral nucleocapsid
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HCV Genome
• 9.6 kb positive strand RNA genome
• 5’ (with IRES) and 3’ noncoding regions
• Open reading frame encoding polyprotein of ~3000 amino acids
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C
E1
E2
p7
NS2
NS3
NS4A
NS4B
NS5A
NS5B
Core protein (nucleocapsid)
Envelope glycoprotein-1
Envelope glycoprotein-2
Viroporin ?
Zn-dependent proteinase
Zn-dependent proteinase, serine protease, helicase
NS3 cofactor
ER-derived membranous web formation
Unknown function; component of replicase?
RNA dependent RNA polymerase
HVR-1
HVR-2
5’ UTR
3’ UTR
ORF
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Protein F
• Newly discovered protein F
• Produced by ribosomal frameshift mutation around codon 11 of Core protein
• Infected individuals contain antibodies
• Function unknown
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Hepatitis C Life Cycle
www.rockefeller.edu/pubinfo/hepc.jpg
CD81?
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Outline
• Epidemiology
• Introduction to Hepatitis C Virus
• Immune response
• Novel drug therapies
• Conclusions
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Patterns of Viremia
1. Drop after peak successful control
2. Drop followed by rebound chronic infection
3. Consistent HCV chronic infection
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Innate Immune Response
2 days after infection:• Protein kinase R (PKR) • Interferon regulatory factors (IRFs)• Antiviral gene products (type I IFN-
inducible genes and immune TFs)
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PKR PKR
dsRNA
PKR activated
IRFs
phosphorylation of IRFs
IRFs act as transcription factorsto upregulate antiviral gene products
Gene products degrade viral RNAand prohibit protein translation
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Innate Immune Response
• Regardless of infection outcome• Viral resistance • Targeting by HCV proteins?
– NS5A and E2 (PKR)– Core (JAK-STAT pathway)– NS3/4A (phosphorylated IRF-3)
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Adaptive Immune Response
Individuals who control virus:
• IFN-γ preferentially expressed in liver
• Induces expression of – genes encoding chemokines that
attract T cells into inflamed tissues– proteins associated with antigen
processing and presentation
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CD8+ and CD4+ T cells
• More vigorous CD8+ and CD4+ T cell responses in all individuals that controlled infection
• Chronic infections occur when– unable to mount HCV-specific T cell
responses– strong response that results in viral
RNA clearance, followed by contraction in CD8+/CD4+ and rebound in viremia
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Chronic HCV infection
• Low frequencies and reduced capacity of HCV-specific CD8+ cells
• Dendritic cells do not mature normally and have impaired stimulatory activity
• CD4+ cells have
reduced IL-2
production and
proliferation
http://www.lbl.gov/Publications/Currents/Archive/Oct-03-2003.html
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Chronic HCV Infection
• Impairment of Natural Killer (NK) cell cytotoxic activity– Reversible in patients responsive to
IFN-α drug therapy
• Frequency of NKT cells decreased
NKT cells (orange) attacking an infected cell (pink)http://www.spectroscopynow.com/ftp_images/killertcells.jpg
Natural Killer cellhttp://www.wasatchhealth.com/images/NK-Picture.jpg
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Antibodies
• Role of antibodies unclear and poorly studied
• Virus can be cleared in absence of detectable antibody responses
• Neutralizing antibodies target E2, which is highly variable and able to evade
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Immune-mediated liver injury
• Mechanisms responsible for liver injury poorly understood
• Host immune response and not viral replication
• High CD8+ in liver immunopathogenesis and liver injury
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Liver Environment
Normal liver:
• “Immuno-silent” state
• CD8+ T cells trapped apoptosis
• Prevents unnecessary immune response to thousands of antigens liver is exposed to
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Liver Environment
HCV-infected liver:
• Type I IFN production
• Release of chemokines that promote infiltration of NK cells
• Induced IFN-γ production in NK cells
• Expression of chemokines that recruit activated T cells to liver
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Liver Environment
Depletion of NK cells before hepatotropic viral infection leads to inhibition of virus-specific T cell response and liver injury
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Immune-mediated liver injury
• HCV infects only 1-10% of hepatocytes
• IFN-γ and TNF-α from CD8+ destroy nearby non-infected hepatocytes (“bystander killing”)
• HCC occurs mainly
due to high turnover
rate in hepatocytes
http://medicalimages.allrefer.com/large/hepatocellular-cancer-ct-scan.jpg
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Outline
• Epidemiology
• Introduction to Hepatitis C Virus
• Immune response
• Novel drug therapies
• Conclusions
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Current therapy
• Combination pegylated interferon-α and ribavirin (nucleoside analog)
• Mechanism poorly understood
• Protein synthesis suppression; degradation of plus strand RNA
• 50-80% effective
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Current therapy
Side effects:• Flu-like symptoms, tiredness, hair loss,
trouble with thinking, moodiness, and depression
• Hematologic– Anemia– bone marrow suppression by IFN
neutropenia, thrombocytopenia– ribavirin directly toxic to red blood cells
hemolysis
• Worsening of liver disease
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Novel drug therapies
• Non-nucleoside inhibitors (NNIs)
• Protease inhibitor
• TGF-β
• Cyclosporin A
• Arsenic trioxide
• RNA therapieis
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Non-nucleoside Inhibitors
• Target RdRp
• Discovery method
• Structurally distinct:– Benzothiadiazine– Disubstituted phenylalanine– 2 benzimidazole derivatives
• Allosteric inhibition
• Distinct binding sites
http://www.replizyme.com/images/rev_rna_hep_c.gif
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Protease Inhibitor• BILN 2061—NS3 protease inhibitor• Peptidomimetic• Oral ingestion• Clinical trial:
– Rapid decline in viral load– Rebound
4-11 days after treatment
http://web.chemistry.gatech.edu/~williams/bCourse_Information/6521/protein/images/hcvmac1.gif
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Transforming growth factor-β
• Naturally occurring cytokine induced by core protein
• Direct effect on HCV replication unknown
• Decreased viral load
• Increased fibrosis and cirrhosis
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Cyclosporin A
• Immunosuppressive drug• Mechanism unknown • FK506 does not suppress HCV
replication• CsA binds to cyclophilins and blocks
calcineurin
inhibits stimulation
of genes essential
for T cell activation• Combination with IFN
http://www.alexis-corp.com/files/formula/lkt-c9611.gif
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Arsenic Trioxide
• Inhibits HCV replication at submicromolar concentrations
• Non-toxic
• Combination with IFN
• Mechanism unknown
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RNA treatments
• Treatments that use RNA to halt viral replication
• Three treatments in development:– RNA interference (RNAi) to degrade
viral RNA– Small RNAs to bind to viral proteins – RNAs to outcompete viral proteins for
binding to cellular proteins
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RNAi
http://www.life.uiuc.edu/shapiro/RNAipathway.jpg
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RNAi
http://www.life.uiuc.edu/shapiro/RNAipathway.jpg
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RNAi
• Inhibits HCV replication
• Highly sequence specific (to 1 nt)
• Multiple siRNAs to target different sites of viral genome
• Short hairpin RNAs targeting conserved motifs encoded by retroviruses
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Small RNAs
• Overexpression of viral RNA elements
• Bind to viral regulatory proteins and prevent binding of viral RNA inhibits gene expression
• RNAs analogous to 5’ UTR inhibited IRES-mediated translation
• Combats sequence specificity problem
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siRNAs
• siRNAs targeted to cellular cofactors for HCV– La, PTB, hVAP-33
• Blocks HCV replication
• Combats sequence specificity problem
• Adenoviral-mediated expression
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Conclusions
• HCV is a major worldwide health concern
• Much remains unknown about HCV• Current drug therapy is inadequate
and insufficient• Novel therapies offer IFN-resistant
patients and those with serious side effects hope of elimination of hepatitis C infection
http://www.english.bayerconosur.com/noticias/tema008-1.asp
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References• Ahmad, A. and Alvarez, F. (2004). Role of NK and NKT cells in the
immunopathogenesis of HCV-induced hepatitis. Journal of Leukocyte Biology 76: 743-759.
• CDC FAQ: http://www.cdc.gov/ncidod/diseases/hepatitis/c/faq.htm• Forns, X. and Bukh, J. (1999). The Molecular Biology of Hepatitis C
Virus: Genotypes and Quasispecies. Clinics in Liver Disease 3.• Guo, J., Sohn, A., Zhu, Q. and Seeger, C. (2004). Mechanism of the
interferon alpha response against hepatitis C virus replicons. Virology 325: 71-81.
• Hwang, D. et al (2004). Inhibition of hepatitis C virus replication by arsenic trioxide. Antimicrobial Agents and Chemotherapy 48: 2876-2882.
• Kowdley, K.V. (2005). Hematologic side effects of interferon and ribavirin therapy. Journal of Clinical Gastroenterology 39, Suppl 1: S3-S8.
• Kronke, J., Kittler, R., Buchholz, F., Windisch, M.P., Pietschmann, T., Bartenschlager, R. and Fresei, M. (2004). Alternative approaches for efficient inhibition of hepatitis C virus RNA replication by small interfering RNAs. Journal of Virology 78: 3436-3446.
Slide template picture: http://www.english.bayerconosur.com/noticias/tema008-1.asp
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References• Lamarre, D. et al (2003). An NS3 protease inhibitor with antiviral effects
in humans infected with hepatitis C virus. Nature 426: 186-189.• Liver Foundation: http://www.liverfoundation.org/db/articles/1028• Mercer D, Schiller D, Elliot J, Douglas DN, Hao C, Rinfret A, Addison
WR. (2001) Hepatitis C virus replication in mice with chimeric human livers. Nat Med 7: 927-933.
• Moradpour, D., Cerny, A., Heim, M.H. and Blum, H.E. (2001). Hepatitis C: an update. Swiss Medical Weekly 131: 231-298.
• Moradpour, D. and Blum, H.E. (2004). A primer on the molecular virology of hepatitis C. Liver International 24: 519-525.
• Murata, T., Ohshima, T., Yamaji, M., Hosaka, M., Miyanari, Y., Hijikata, M. and Shimotohno, K. (2005). Suppression of hepatitis C virus replicon by TGF-β. Virology 331: 407-417.
• Nakagawa, M. et al (2004). Specific inhibition of hepatitis C virus replication by cyclosporine A. Biochemical and Biophysical Research Communications 313: 42-47.
• Penin, F., Dubuisson, J., Rey, F.A., Moradpour, D. and Pawlotsky, J. (2004). Structural Biology of Hepatitis C Virus. Hepatology 39: 5-19.
• Puig, M., Major, M.E., Mihallik, K. and Feinstone, S.M. (2004). Immunization of chimpanzees with an envelope protein-based vaccine enhances specific humoral and cellular immune responses that delay hepatitis C virus infection. Vaccine 22: 991-1000
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References
• Ray, P.S. and Das, S. (2004). Inhibition of hepatitis C virus IRES-mediated translation by small RNAs analogous to stem-loop structures of the 5’-untranslated region. Nucleic Acids Research 32: 1678-1687.
• Sarisky, R.T. (2004). Non-nucleoside inhibitors of the HCV polymerase. Journal of Antimicrobial Chemotherapy 54: 14-16.
• Shoukry, N.H., Cawthon, A.G. and Walker, C.M. (2004). Cell-mediated immunity and the outcome of hepatitis C virus infection. Annual Reviews in Microbiology 58: 391-424.
• Sun, J., Li, K., Shata, M.T. and Chan, T. (2004). The immunologic basis for hepatitis C infection. Current Opinions in Gastroenterology 20: 598-602.
• Trujillo-Murillo, et al. (2004). Experimental models for hepatitis C virus (HCV): New opportunities for combating hepatitis C. Annals of Hepatology 3: 54-62.
• World Health Organization (WHO) (1999). Weekly Epidemiological Record No. 49, December.
• Zhang, J., Yamada, O., Sakamoto, T., Yoshida, H., Iwai, T., Matsushita, Y., Shimamura, H., Araki, H. and Shimotohno, K. (2004). Down-regulation of viral replication by adenoviral-mediated expression of siRNA against cellular cofactors for hepatitis C virus. Virology 320: 135-143.