The mechanism of hcv extrahepatic infection
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The mechanism of HCV extrahepatic infection. Michael M.C. Lai Institute of Molecular Biology Academia Sinica. Sept. 21, 2012 at Wuhan. Clinical manifestations of HCV. Evidence that PBMC infection by HCV is causally linked to B cell lymphoma.

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The mechanism of HCV extrahepatic infection

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The mechanism of hcv extrahepatic infection

The mechanism of HCV extrahepatic infection

Michael M.C. Lai

Institute of Molecular Biology

Academia Sinica

Sept. 21, 2012 at Wuhan


Clinical manifestations of hcv

Clinical manifestations of HCV


Evidence that pbmc infection by hcv is causally linked to b cell lymphoma

Evidence that PBMC infection by HCV is causally linked to B cell lymphoma

  • High frequency of HCV infection (20-40%) among B-cell lymphoma patients in some geographical regions

  • HCV-transgenic mice develop B-cell lymphoma (Kasama et al. 2011)

  • Antiviral therapy (interferon plus ribavirin) of HCV(+) lymphoma patients can induce tumor remission (Hermine et al., 2002: Levine et al., 2003)

  • A lymphotropic HCV (SB virus) was isolated from a B-cell lymphoma (Sung et al., 2003)


The mechanism of hcv extrahepatic infection

A lymphotropic HCV (HCV-SB) isolated from a B-cell lymphoma

  • Isolated from the spleen of an HCV-positive patient with B-cell lymphoma and mixed cryoglobulinemia

  • HCV-SB virus particles can infect B cells and T cells but not hepatocytes.

  • HCV-SB has typical characteristics of hepatotropic HCV strains


Candidate hcv receptors

Candidate HCV receptors

  • CD81

    • ubiquitous, initial virus binding

  • SR-B1 (scavenger receptor B1)

    • Hepatocyte, dendritic cells

  • LDLR

    • ubiquitous

  • L-SIGN, DC-SIGN

    • LSEC, Kupffer cells

  • Glycosaminoglycans (heparan sulfate)

  • Claudin-1, Occludin (entry molecules)

    • tight junction molecules (liver, epithelial cells)


The mechanism of hcv extrahepatic infection

Hecker, E. & Ott, M. 2011. Ubique ties between hepatitis C virus replication and intracellular lipids. Cell. 22(6).243


The mechanism of hcv extrahepatic infection

Molecular mechanism of viral lympho- vs hepatotropism

T7 in vitro

transcripts

Electroporation

into Huh7.5 and Raji

Detection (qRT-PCR)

Harvest

Cloned cDNA


The mechanism of hcv extrahepatic infection

SB virus RNA, but not JFH-1 Virus, Replicates in Raji Cells

m

m

Raji


Jfh 1 virus but not sb virus rna replicates in huh7 5 cells

JFH-1 Virus, but not SB Virus RNA, Replicates in Huh7.5 Cells

m

m

Huh7.5

  • SB virus is lymphotropic. JFH1 virus is hepatotropic.


The mechanism of hcv extrahepatic infection

Chimera Virus containing E1-E2 of SB Strain Produces High Levels of HCV RNA in Raji Cells

150000


The mechanism of hcv extrahepatic infection

Infection of target cells

GFP orluciferase expression

HCVpp entry

Rajior Huh7.5

Study virus entry, receptors, host range, etc.

HCV Pseudoparticle System (HCVpp)

A retrovirus reporter virus with HCV envelope proteins

HCVE1/E2

gag-pol (retrovirus)

y

GFP or Luciferase


The mechanism of hcv extrahepatic infection

Infectivity of HCV Pseudo-particles is Determined

by E1-E2 of SB Strain in Raji Cells

FACS for GFP reporter with HCVpp at 72 h p.i

Normalized for p24 HIV core antigen

Raji

1/100

1/100

Huh7.5


Anti cd81 and ifn treatment inhibit hcv replication

Anti-CD81 and IFN Treatment Inhibit HCV Replication


Consequences of hcv infection of b cells

Consequences of HCV infection of B cells

  • Inhibition of DNA damage repair: chromosomal translocation

  • Uncoupling of mitotic checkpoint: chromosomal polyploidy

  • Induction of error-prone DNA polymerases: hypermutation of immunoglobulin and protooncogenes


The mechanism of hcv extrahepatic infection

iNOS

inhibitor

1400W

Mutation

frequency

X10-4

HCV

infection

% clones

mutated

Locus

p53

-

+

+

-

-

+

0 (0/18)

15 (3/20)

0 (0/20)

0

7.25

0

VH

-

+

+

-

-

+

15 (3/20)

55 (11/20)

35 (7/20)

4.1

20.3

9.6

Mutation frequencies of p53 and VH

in HCV-infected human B cell lines


Higher mutation frequency in oncogenes in hcv associated b cell lymphoma and hcc

Higher mutation frequency in oncogenes in HCV-associated B cell lymphoma and HCC

Mutation frequency

(mutation/bp) x10-4

p53 -catenin

HCV-associated

Non-HCV

HCV

tumor

nontumor

HBV

tumor

nontumor

Nonviral tissues

30

3.9

35

5.9

3.9

0

2.5

33

0

30

11

7.4 7.4

4.4

B cell

lymphomas

Hepatocellular

carcinomas

(HCC)


Hcv sb also infects t cells and suppresses interferon signaling

HCV-SB also infects T cells and suppresses interferon signaling


Extrahepatic infection particularly pbmc infection plays an important role in hcv pathogenesis

Extrahepatic infection, particularly PBMC infection, plays an important role in HCV pathogenesis


Acknowledgment

Acknowledgment

  • Keigo Machida

    • University of Southern California

  • Chao Kuen Lai

  • King-Song Jeng

    • Academia Sinica, taiwan


Thanks for your attention

Thanks for your attention.


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