the innate and adaptive immunology of HCV

1. HCV
Ahmed Elsherbini

2. Outline:
• Introduction.
• Life cycle and Spaces.
• Expected.
• Evidence based Literature and Text books.
• Which immune responses are believed to be protective..?
• Vaccine.
• Abbreviation.
• References.
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3. Introduction*
• The hepatitis C virus is ssRNA virus.
• Has 6 genotypes.
• Frequency 143 million and Deaths=496,000
• Human and chimpanzee only.
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4. 4
• consists of a core of (RNA),
surrounded by protective shell
of protein encased in a lipid
envelope of cellular origin.
• Two envelope Glycoprotien E1
and E2, are embedded in the
lipid envelop.
Introduction (cont.)
Structure:

5. Introduction(cont.)
Pathology
15% of cases develop
acute. But, rarely
does have liver failure .The
infection resolves
spontaneously more
frequently in young and
females.
85% of cases develop a
chronic infection .they
experience minimal
symptoms during the
initial stage but, after
several years they may
have cirrhosis or HCC.
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6. Spaces and life cycle
The virus replicates mainly in the hepatocytes cytoplasm (ER) of liver but, may
also replicate in peripheral blood mononuclear cells.
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7. Expected immunity.
Innate immunity:
• Liver Macrophage ,DCs and NK cells as they are enriched in liver may play a role…
• Interferons as the main cytokines.
Adaptive immunity:
• CD 4 TH1 > TH2
• CD 8 cytotoxic (CMI) may be the main effector agent against HCV..
• Antibodies may have a role as virus present in blood and ADCC..
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8. Evidence based Literature and
Text book
Innate
Immunity
Adaptive
immunity
How could
HCV evade.!
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9. Evidence based literature and text book (cont.)
General scheme of 8 steps…! *
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10. Evidence based –Innate immunity (cont.)
Step number (1)
The first line of immunity against
HCV relies on cell-intrinsic innate
immunity within hepatocyte cells .
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11. PRR PAMP
1-RIG-I ,pkr-1
(Cytosolic PRR)
dsRNA
from the Internal ribosome entry side.
from accumulation after HCV infection
from dying cells later.
2-TLR 3 dsRNA
3-TLR 7,8* ssRNA
Evidence based-Innate Immunity (cont.)
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12. Evidence based innate
immunity (cont.)
Viral RNA sensing by
RIGs -> MAVS-->
IRF3,7ISG .
INF β,γ.
Similar, occurs by
viral RNA sensing by
TLR3TRIFISG..
INF β,γ .
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13. 13
Evidence based-Innate
immunity (cont.)
Hepatic DC , APC
step number (2)
• Liver resident and migratory APCs
uptake apoptotic bodies from
destroyed HCV-infected
hepatocytes and present HCV
derived epitopes to both CD4 and
CD8 T cell in the context of MHC
class II and MHC class I ,
respectively.
Liver
Macrophage
Kupffer cells
Circulating
macrophage

14. Evidence based Innate Immunity (cont.)
Controversy of DCs…!
function of DCs is controversial…!
1-recently demonstrated that sustained hyperresponsiveness of DCs was associated with
resolution of HCV infection  better priming of HCV-specific T cells.*
2-Another groups Also, have reported that DCs are defective in HCV response to and may
induce proliferation of T reg chronic infection.**
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15. Evidence based Innate Immunity (cont.)
KCs and fibrosis…!
• KCs produce profibrogenic factors and yet also represent a major source of matrix
breakdown and turnover -cirrhosis.
• Nitric oxide produced by activated KCs may also promote DNA damage HCC .
• it has recently been postulated that KC-derived IL-6 contributes to HCC development
so, Estrogen inhibition of IL-6 production MAY reduces HCC risk in females.*
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16. Evidence based Innate immunity (cont.)
Step number (3) …NK cells
• NK cells are highly enriched in the liver and are expected to play a major role in
controlling hepatotropic infections.
• NK cells from acutely infected individuals and during chronic infection were
biased toward cytotoxicity rather than cytokine production.
• ADCC..!
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17. Evidence based Adaptive immunity (cont.)
Step number (4)…CD4
• HCV-specific CD4 and CD8 T cell appear late around 6–8 weeks after primary HCV
infection May be indicative of the capacity of the virus to evade the innate
immune system.
• CD4 helper T cell support responses of CD8T cells and B cell through production
of Th1 and Th2 cytokine respectively.
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18. Evidence based Adaptive Immunity (cont.)
Step number (5) …..Neutralizing Antibodies
• Most of these Abs have NO antiviral activity. However, only a small subset is able
to prevent virus binding, entry or post-entry steps of the viral lifecycle.
• ADCC is not fully understood ,also the role of Tfh * cells in this process is still
unknown.
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19. Evidence based Adaptive Immunity (cont.)
Step number (6)…CD8
• The main adaptive effector cells involved in HCV clearance.
• CD8 T cells eliminate HCV-infected cells through direct cytotoxic
mechanisms(granules, perforin and granzyme) or non-cytolytic mechanisms
through secretion of the antiviral cytokines IFN g and TNF a.
• But,CD8 needs to persists its action…!
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20. Evidence based adaptive (cont.)
Exhausted CD8…!
T17/ Treg Balance
Step number (7)..T17
Early induction of IL-21 producing Th17 cells is
critical to limit exhaustion of CD8 T cells
Step number (8) ..T reg
T reg contributes to exhaustion
and inhibition of CD4 and CD8
through production of the Tim-
3,Gal-9 ,IL-10 and TGF-B
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21. HCV Evasion of innate immunity
The Swiss Army knife..!
NS3-NS4A is serine protease activity to block RIG-I and TLR3 By splicing MAVS and
TRIF downstream -prevents activation of the pathway during acute infection
abrogates IFN induction  Delay in Adaptive response ...!
What about NK cells….!
Recombinant HCV E2 protein was reported to directly bind CD81 on the surface of
NK cells  inhibit its functions.
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22. HCV Evasion of innate immunity (cont.)
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23. HCV Evasion from Adaptive
Immunity (cont.)
from neutralizing antibodies
• Escape mutations  quasispecies.
• direct cell–cell transmission
CD8+ T cell dysfunction
• Escape mutations For CD8+ T cell
epitopes.
• lack of CD4+ help may contribute to CD8+
T cell dysfunction.
• Impaired production of antiviral cytokines
as by suppression regulatory T cells.
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24. HCV Evasion from Adaptive immunity (cont.)
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25. Which immune responses are believed to be protective.!
Studies of depletion..!
• One study of CD4 depletion in chimpanzees ,first they temporarily
controlled viremia then viral titers increased again and These data supports
the concept that HCV-specific CD8 T cells are the main antiviral effector cells
while HCV specific CD4 T cells have important helper functions to prevent
viral escape from the CD8 T cell response..*
• HCV and HIV co-infection..!**
• One study of KC depletion leading to attenuated liver injury…!***
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26. Vaccine.
• No approved vaccine of HCV.
• Some trials working to include several components of the adaptive immune
response as successful vaccination strategy because, vaccine-induced CD8+ T
cell responses may fail when sufficient CD4+ T cell help is missing.
• Regarding therapeutic immune strategies, restoration of CD8+ T cell
function may be a promising concept.
• 2013 The revolution of new HCV drugs (sofosbuvir) and preventive
medicine..!
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27. Abbreviation.
• HCC : Hepatocellular carcinoma.
• KCs: Kupffer cells.
• TRIF:TIR-domain-containing adapter-inducing interferon-β
• T fh : follicular helper cells
• RIG-1: Retinoic Acid Inducible Gene 1 protein.
• PKR-1: Protein kinase receptor.
• MAVS: mitochondrial antiviral signaling protein.
• TBK-1: Serine/threonine-protein kinase .
• IRF: Interferon regulatory factor.
• ISG : interferon stimulating gene.
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28. References.
• Eui-Cheol Shin, Pil Soo Sung & Su-Hyung Park et, Nature Reviews
Immunology 16, 509–523.
• Lynn B. Dustin, Curr Drug Targets. 2017; 18(7): 826–843.
• S. Abdel-Hakeem ,H. Shoukry , Front Immunol. 2014; 5: 274.
• Ralf Bartenschlager,Springer. Berlin, 2013
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